Osmotic Delivery Systems and Piston Assemblies for Use Therein

ABSTRACT

An osmotic delivery system is disclosed for delivering an active agent formulation to a fluid environment. The osmotic delivery system typically comprises a reservoir having a lumen that contains the active agent formulation and an osmotic agent formulation and a piston assembly positioned in the lumen to isolate the active agent formulation from the osmotic agent formulation. The piston assembly typically comprises a body constructed and arranged for positioning in the lumen. The body is typically made of a polymeric material that is, for example, resistant to leaching in an organic solvent. In one embodiment, the body is a columnar body having a rim at a distal end thereof for engaging and sealing against a wall of the reservoir and the piston assembly further comprises a spring retained at the distal end of the columnar body for biasing the rim of the columnar body against the wall of the reservoir.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/930,950, filed 19 Jan. 2011, which is a continuation of U.S. patentapplication Ser. No. 12/658,570, filed 9 Feb. 2010, now U.S. Pat. No.7,879,028, which is a continuation of U.S. patent application Ser. No.11/890,836, filed 8 Aug. 2007, now U.S. Pat. No. 7,682,356, which claimsthe benefit of U.S. Provisional Application Ser. No. 60/821,830, filed 9Aug. 2006, now expired, and U.S. Provisional Application Ser. No.60/930,205, filed 15 May 2007, now expired, all of which applicationsare herein incorporated by reference in their entireties.

TECHNICAL FIELD

The invention relates generally to osmotic delivery systems forsustained delivery of active agents in fluid environments. Morespecifically, the invention relates to a piston assembly used in forminga partition in the lumen of a reservoir of an osmotic delivery system.

BACKGROUND OF THE INVENTION

In osmotic delivery systems such as described in U.S. Pat. No. 5,728,396and U.S. Pat. No. 6,524,305, a piston is positioned in the lumen of areservoir to divide the lumen of the reservoir into two chambers. Thefirst chamber contains an osmotic agent formulation while the secondchamber contains an active agent formulation. The piston isolates theosmotic agent formulation from the active agent formulation by engagingand sealing against the wall of the reservoir. Pressure differentialacross the piston allows the piston to move longitudinally within thereservoir. The piston is generally required to maintain its seal withthe wall of the reservoir as it moves within the reservoir. The pistonis typically made of a material that is of lower hardness than thereservoir, that will deform to fit the lumen of the reservoir, and thatis impermeable. Typically, the piston is made of an elastomericmaterial, examples of which include, but are not limited to, thefollowing: polypropylene; rubbers such as ethyl propylene diene rubber,silicone rubber, butyl rubber, chlorinated rubber, styrene-butadienerubber, or chloroprene rubber; and thermoplastic elastomers such asplasticized polyvinylchloride, polyurethane, SANTOPRENE® (AdvancedElastomer Systems, Akron Ohio), or C-FLEX® (Consolidated PolymerTechnologies, Inc., Clearwater Fla.).

There continues to be a desire to improve compatibility and sealing ofpistons with components of the osmotic delivery systems.

SUMMARY OF THE INVENTION

The present invention relates to osmotic delivery systems, active agentformulations for use therein, as well as methods of making and methodsof using the osmotic delivery systems. The present invention alsorelates to pistons and piston assemblies. In some embodiments thepistons and piston assemblies are substantially resistant to leachingwhen contacted with an organic solvent or solutions comprising organicsolvents, for example, suspension vehicles.

In one aspect, the invention relates to an osmotic delivery system fordelivering an active agent formulation in a fluid environment. Theosmotic delivery system comprises a reservoir comprising a lumen thatcontains the active agent formulation, an osmotic agent formulation, anda piston assembly positioned in the lumen to isolate the active agentformulation from the osmotic agent formulation. The piston assemblycomprises a body, for example, a columnar body, constructed and arrangedfor positioning in the lumen. The body is typically made of materialthat is resistant to leaching in an organic solvent, for example, apolymeric material. The body further comprising means for engaging andsealing against a wall of the reservoir.

In one embodiment of the osmotic delivery system, the body of the pistonassembly is substantially columnar and comprises a rim at a distal endthereof for engaging and sealing against the wall of the reservoir, aswell as a spring retained at the distal end for biasing the rim againstthe wall of the reservoir. The spring may be retained in a cavity at thedistal end of the columnar body. The spring may be, for example, aradial spring such as a canted coil spring. Typically the spring is madeof a non-reactive metal. One or more such combination of a rim and ringmay be present along the body of the piston, for example, at one distalend, at each distal end, or at one or more distal end with one or moresuch combinations distributed along the body of the piston between thedistal ends.

In another embodiment of the osmotic delivery system, the pistonassembly may comprise a body constructed and arranged for positioning inthe lumen, the body being made of a material that is resistant toleaching in an organic solvent (e.g., a suitable polymeric material).The piston assembly can, for example, further comprises one or moreconcentric grooves, each groove formed to retain an elastomeric O-ringthat provides the means for engaging and sealing against the wall of thereservoir.

In another aspect, the invention relates to a piston assembly forpositioning in a lumen of a reservoir for an osmotic delivery system.The piston assembly comprises a body, for example, a columnar body,constructed and arranged for positioning in the lumen, the body beingmade of a material (e.g., a suitable polymeric material) that isresistant to leaching in an organic solvent, wherein the body furthercomprises means for engaging and sealing against a wall of thereservoir.

In one embodiment of the piston assembly, the body is substantiallycolumnar and comprises a rim at a distal end (or, in another embodiment,a rim at each distal end) of the piston assembly for engaging andsealing against the wall of the reservoir, and a spring retained at thedistal end (or at both distal ends) for biasing the rim against the wallof the reservoir. Further, one or more springs may be retained betweenthe distal ends of the piston assembly providing one or more rim forengaging and sealing against the wall of the reservoir. Thus the pistonassembly may comprise one or more means for engaging and sealing againstthe wall of the reservoir placed at various locations along the lengthof the piston assembly with, preferably, at least one such means nearthe distal end of the piston that comes into contact with the chamber ofthe reservoir that comprises organic solvent (e.g., the chambercomprising the active agent formulation).

Springs useful in the practice of the present invention include radialsprings such as canted coil springs, for example, made of metal that isnon-reactive with other components of the osmotic delivery system (inparticular, non-reactive with the active agent formulation and/or theosmotic agent formulation).

In another embodiment of the piston assembly, the piston assemblycomprises a body constructed and arranged for positioning in the lumen,wherein the body is made of a material that is resistant to leaching inan organic solvent and comprises one or more concentric grooves.Typically, each groove is formed to retain an elastomeric O-ring thatprovides the means for engaging and sealing against the wall of thereservoir.

In another aspect the present invention relates to an osmotic deliverysystem loaded with an active agent comprising one or more peptide,polypeptide or protein (e.g., a particle suspension comprising one ormore peptide particles, polypeptide particles, or protein particles). Inone embodiment the peptide is an interferon, for example, an interferonselected from the group consisting of alpha interferon, beta interferon,delta interferon, gamma interferon, lambda interferon, omega interferon,tau interferon, and mixtures thereof. The active agent can be, forexample, a suspension formulation comprising (i) a particle formulationof peptide particles (e.g., comprising interferon), and (ii) suspendedin a vehicle comprising a solvent (e.g., an organic solvent) andpolymer.

In another aspect the present invention relates to the treatment ofinterferon-responsive disease states using the osmotic delivery systemof the present invention loaded with an active agent comprisinginterferon. In one embodiment, the present invention relates to a methodof treating hepatitis C virus (HCV) infection in a subject in need ofsuch treatment, comprising administering an osmotic delivery system ofthe present invention loaded with a suspension formulation comprisingalpha, beta, or omega interferon (e.g., a particle formulationcomprising the selected interferon) to the subject. In anotherembodiment, the present invention relates to a method of treatingmultiple sclerosis in a subject in need of such treatment, comprisingadministering an osmotic delivery system of the present invention loadedwith a suspension formulation comprising beta or omega interferon (e.g.,a particle formulation comprising the selected interferon) to thesubject.

In another aspect the present invention relates to the treatment ofdiabetes and/or diabetes-related diseases using the osmotic deliverysystem of the present invention loaded with an active agent comprisingan insulinotropic peptide. In one embodiment, the present inventionrelates to a method of treating diabetes in a subject in need of suchtreatment, comprising administering an osmotic delivery system of thepresent invention loaded with a suspension foirmulation comprisingglucagon like protein 1 (GLP-1) or exendin-4 (e.g., a particleformulation comprising the GLP-1 or exendin-4) to the subject.

These and other embodiments of the present invention will readily occurto those of ordinary skill in the art in view of the disclosure herein.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, described below, illustrate typicalembodiments of the invention and are not to be considered limiting ofthe scope of the invention, for the invention may admit to other equallyeffective embodiments. The figures are not necessarily to scale, andcertain features and certain view of the figures may be shownexaggerated in scale or in schematic in the interest of clarity andconciseness.

FIG. 1 depicts a cross-sectional view of an osmotic delivery systemincluding a piston assembly.

FIG. 2A is an enlarged view of the piston assembly of FIG. 1.

FIG. 2B depicts a cross-sectional view of a piston assembly having duallip-seals.

FIG. 3 depicts cumulative release of an active agent formulation overtime using the piston assembly of FIG. 2A.

FIG. 4A depicts a side view of a piston assembly having two O-ring typesealing members.

FIG. 4B presents a schematic side view of the piston assembly of FIG.4A.

FIG. 4C depicts a side view of a piston assembly having three O-ringtype sealing members.

DETAILED DESCRIPTION OF THE INVENTION

All patents, publications, and patent applications cited in thisspecification are herein incorporated by reference as if each individualpatent, publication, or patent application was specifically andindividually indicated to be incorporated by reference in its entiretyfor all purposes.

1.0.0 DEFINITIONS

It is to be understood that the terminology used herein is for thepurpose of describing particular embodiments only and is not intended tobe limiting. As used in this specification and the appended claims, thesingular forms “a,” “an” and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “apolymer” includes a combination of two or more such polymers, referenceto “an active agent” includes one or more active agent, mixtures ofactive agents, and the like.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains. Although other methods andmaterials similar, or equivalent, to those described herein can be usedin the practice of the present invention, the preferred materials andmethods are described herein.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

The phrase “active agent” as used herein typically refers to apharmacologically useful compound, including, but not limited to, smallmolecules, peptides, and combinations thereof.

The terms “peptide,” “polypeptide,” and “protein” are usedinterchangeable herein and typically refer to a molecule comprising achain of two or more amino acids (e.g., most typically L-amino acids,but also including, e.g., D-amino acids, modified amino acids, aminoacid analogues, and/or amino acid mimetics). Peptides, polypeptides, andproteins may also comprise additional groups modifying the amino acidchain, for example, functional groups added via post-translationalmodification. Examples of post-translation modifications include, butare not limited to, acetylation, alkylation (including, methylation),biotinylation, glutamylation, glycylation, glycosylation,isoprenylation, lipoylation, phosphopantetheinylation, phosphorylation,selenation, and C-terminal amidation. The terms peptides, polypeptides,and proteins also include modifications of the amino terminus and/or thecarboxy terminus. Modifications of the terminal amino group include, butare not limited to, des-amino, N-lower alkyl, N-di-lower alkyl, andN-acyl modifications. Modifications of the terminal carboxy groupinclude, but are not limited to, amide, lower alkyl amide, dialkylamide, and lower alkyl ester modifications (e.g., wherein lower alkyl isC₁-C₄ alkyl).

The term “amino acid” as used herein typically refers to naturallyoccurring and synthetic amino acids, as well as amino acid analogs andamino acid mimetics that function in a manner similar to the naturallyoccurring amino acids. Naturally occurring amino acids include thoseencoded by the genetic code, as well as amino acids formed by latermodification, for example, hydroxyproline, gamma-carboxyglutamate, andO-phosphoserine.

The term “amino acid analogs” as used herein typically refers tocompounds that have the same basic chemical structure as a naturallyoccurring amino acid (e.g., a carbon that is linked to: a hydrogen, acarboxyl group, an amino group, and an R group). Examples of amino acidanalogs include, but are not limited to, homoserine, norleucine,methionine sulfoxide, or methionine methyl sulfonium. Such analogsgenerally have modified R groups (e.g., norleucine) or modified peptidebackbones, but retain the same basic chemical structure as a naturallyoccurring amino acid.

The term “amino acid mimetics” as used herein typically refers tochemical compounds that have a structure that is different from thegeneral chemical structure of an amino acid, but that function in amanner similar to a naturally occurring amino acid.

The terms “peptide mimetics” or “peptidomimetics” as used hereingenerally refer to active agents that are structurally similar totherapeutically useful peptides and that may be used to produce anequivalent therapeutic or prophylactic effect (Fauchere, J., Adv. Drug.Res. 15, 29-69 (1986); Veber and Freidinger, TINS p. 392-396 (1985); andEvans, et al., J. Med. Chem. 30:1229-1239 (1987)) and are usuallydeveloped with the aid of computerized molecular modeling.Peptidomimetics are typically structurally similar to a referencepolypeptide (i.e., a polypeptide that has a selected biochemicalproperty or pharmacological activity, for example, omega interferon,GLP-1, or exendin-4) but have one or more peptide linkages optionallyreplaced by a linkage selected from, but not limited to, the following:—CH2NH—; —CH2S—; —CH2-; —CH═CH—(cis and trans); —COCH2-, —CH(OH)CH2-, or—CH2SO—. Such linkages are known in the art. Such peptide mimetics mayprovide advantages relative to polypeptide embodiments, for example, byproviding more economical production, greater chemical stability,enhanced pharmacological properties (e.g., half-life, absorption,potency, efficacy, etc.), altered specificity (e.g., a broad-spectrum ofbiological activities), and/or reduced antigenicity.

As used herein the terms “analog polypeptides” or “derivativepolypeptides” typically refer to polypeptides comprising one or moreconservative amino acid substitutions with respect to anaturally-occurring reference sequence. Analog or derivativepolypeptides also refers to amino acid additions or amino acid deletionsrelative to the primary sequence of a reference polypeptide wherein themodification (e.g., amino acid addition or deletion) does notsubstantially, adversely affect the desired property of the analogpolypeptide. Generally polypeptides having one or more amino acidsubstitution, addition, or deletion relative to a reference polypeptidehave substantial identity to the reference polypeptide. The term“substantial identity” as used herein typically means that two peptidesequences, when optimally aligned, such as by the programs GAP orBESTFIT using default parameters (e.g., default gap weights), share atleast about 80 percent sequence identity, preferably at least about 90percent sequence identity, more preferably at least about 95 percentsequence identity, and most preferably at least about 98 percentsequence identity. Preferably, residue positions that are not identicaldiffer by conservative amino acid substitutions.

As used herein the phrase “conservative amino acid substitutions”typically refers to the interchangeability of amino acid residues havingsimilar side chains, for example, a group of amino acids havingaliphatic side chains comprises glycine, alanine, valine, leucine, orisoleucine; a group of amino acids having aliphatic-hydroxyl side chainscomprises serine or threonine; a group of amino acids havingamide-containing side chains comprises asparagine or glutamine; a groupof amino acids having aromatic side chains comprises phenylalanine,tyrosine, or tryptophan; a group of amino acids having basic side chainscomprises lysine, arginine, or histidine; and a group of amino acidshaving sulfur-containing side chains comprises cysteine or methionine.Preferred conservative substitution groups of amino acids include, butare not limited to, valine/leucine/isoleucine (i.e., each of these threemay be substituted at residues where one of them occurs),phenylalanine/tyrosine, lysine/arginine, alanine/valine,glutamic/aspartic, and asparagine/glutamine.

The term “vehicle” as used herein refers to a medium used to carry anactive agent. Vehicles of the present invention typically comprisecomponents such as polymers and solvents. The term “organic solvent” asused herein refers to organic compounds (i.e., containing carbon atoms)used to dissolve another substance (e.g., a polymer). The phrase“suspension vehicle” as used herein typically refers to solvents andpolymers that are used to prepare suspension formulations of, forexample, peptide particles (herein the terms peptide particle,polypeptide particle and protein particle are used interchangeably). Thebodies of the piston assemblies of the present invention are generallymade of one or more polymeric materials and are substantially resistantto leaching in an organic solvent that is included in a vehicle used incombination with a piston assembly.

The phrase “phase separation” as used herein refers to the formation ofmultiple phases (e.g., liquid or gel phases) in the suspension vehicle,such as when the suspension vehicle contacts the aqueous environment. Insome embodiments of the present invention, the suspension vehicle isformulated to exhibit phase separation upon contact with an aqueousenvironment having less than about 50% water, preferably less than about20% water, and more preferably less than about 10% water.

The phrase “single-phase” as used herein refers to a solid, semisolid,or liquid homogeneous system that is physically and chemically uniformthroughout.

The term “dispersed” as used herein refers to dissolving, dispersing,suspending, or otherwise distributing a compound, for example, a peptideparticle, in a suspension vehicle.

The phrase “chemically stable” as used herein refers to formation in aformulation of an acceptable percentage of degradation products producedover a defined period of time by chemical pathways such as deamidation(usually by hydrolysis), aggregation, or oxidation.

The phrase “physically stable” as used herein refers to formation in aformulation of an acceptable percentage of aggregates (e.g., dimers andother higher molecular weight products). Furthermore, a physicallystable formulation typically will not change its physical state as, forexample, from liquid to solid, from amorphous to crystal form, orinter-exchange between polymorphous states.

The term “viscosity” as used herein typically refers to a valuedetermined from the ratio of shear stress to shear rate (see, e.g.,Considine, D. M. & Considine, G. D., Encyclopedia of Chemistry, 4thEdition, Van Nostrand, Reinhold, N.Y., 1984) essentially as follows:

F/A=μ(V/L)  (Equation 1)

where F/A=shear stress (force per unit area),

μ=a proportionality constant (viscosity), and

V/L=the velocity per layer thickness (shear rate).

From this relationship, the ratio of shear stress to shear rate definesviscosity. Measurements of shear stress and shear rate are typicallydetermined using parallel plate rheometry performed under selectedconditions (for example, at a temperature of about 37° C.). Othermethods for the determination of viscosity include measurement of akinematic viscosity using a viscometers, for example, a Cannon-Fenskeviscometer, a Ubbelohde viscometer for the Cannon-Fenske opaquesolution, or a Ostwald viscometer. Generally, suspension vehicles of thepresent invention have a viscosity sufficient to prevent a particleformulation suspended therein from settling during storage and settlingduring use in a method of delivery, for example, in an implantable,osmotic delivery system for delivering an active agent formulation.

The term “non-aqueous” as used herein refers to an overall moisturecontent, for example, of a formulation, typically of less than about 10weight percent (wt %), preferably less than about 5 wt %, and morepreferably less than about 4 wt %.

The phrase “resistant to leaching in an organic solvent” as used hereintypically refers to the generation of an amount of leachates into theactive agent formulation that is acceptable for pharmaceutical use. Anacceptable amount of leachates generally depends on the quantity as wellas toxicity of the leachates and may include determination of otherfactors including, but not limited to, the following: daily dose ofleachates; route of administration (e.g., oral, inhaled, injected, ordelivered from an implanted device); clinical vs. commercial use; andreactivity or interference of leachates with active agent, other devicecomponents, packaging, assays or product functionality. Inpharmaceutical applications the amount and type of leachates aretypically within tolerance limits for the subject who will be exposed tothe leachates. In some embodiments of the present invention, (i)production of volatile leachates (when the piston assembly of thepresent invention is exposed to organic solvent) is less than betweenabout 1.4 μg/ml and about 10 μg/ml, preferably less than about 1.4μg/ml, from polymeric material when exposed to the organic solvent at40° C. for about 45 days, or between about 1.4 μg/ml and about 15 μg/ml,preferably less than about 1.4 μg/ml, from polymeric material whenexposed to the organic solvent at 40° C. for about 90 days or longer,and (ii) production of non-volatile leachates (when the piston assemblyof the present invention is exposed to organic solvent) is less thanbetween about 9.0 μg/ml and about 15 μg/ml, preferably less than about9.0 μg/ml, from polymeric material when exposed to the organic solventat 40° C. for about 45 days, or between about 9.0 μg/ml and about 20μg/ml, preferably less than about 9.0 μg/ml, from polymeric materialwhen exposed to the organic solvent at 40° C. for about 90 days orlonger.

The phrases “sealing member,” “sealing means,” or “sealing device” asused herein generally refer to a device used between two parts (e.g.,chambers) to prevent leakage of fluid between the parts. The sealingdevice is typically made of a flexible material. A sealing memberbetween two chambers of a reservoir is typically water-tight. Examplesof sealing devices include, but are not limited to, a piston assembly(e.g., where a canted coil spring biases a rim of the piston against theinterior wall of the reservoir) or one or more component of the pistonassembly (e.g., an O-ring, gasket, seal, packing, or the like) thatcontacts the inner surface of the lumen of the reservoir to providesubstantial separation between the contents of the active agent chamberof the lumen of the reservoir and contents of the osmotic agent chamberof the lumen of the reservoir. The sealing member or sealing meansprovides substantial separation between two or more fluids containedwithin different regions or chambers of reservoir.

The term “subject” as used herein refers to any member of the subphylumchordata, including, without limitation, humans and other primates,including non-human primates such as rhesus macaque, chimpanzees andother apes and monkey species; farm animals such as cattle, sheep, pigs,goats and horses; domestic mammals such as dogs and cats; laboratoryanimals including rodents such as mice, rats and guinea pigs; birds,including domestic, wild and game birds such as chickens, turkeys andother gallinaceous birds, ducks, geese, and the like. The term does notdenote a particular age. Thus, both adult and newborn individuals areintended to be covered.

2.0.0 GENERAL OVERVIEW OF THE INVENTION

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particular types ofpolymeric materials, particular sources of polymers, particularpolymers, and the like, as use of such particulars may be selected inview of the teachings of the present specification. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments of the invention only, and is notintended to be limiting.

In one aspect, the present invention relates to an osmotic deliverysystem for delivering an active agent formulation to a fluidenvironment, including a piston assembly comprising a body (e.g., acolumnar body). In some embodiments, the piston assembly or componentsof the piston assembly are made of a polymeric material that isresistant to leaching in an organic solvent. In some embodiments, thepiston assemblies of the present invention provide a reliable seal(e.g., a water-tight seal) between the piston assembly and the interiorwall of the reservoir. In some embodiments, the piston assemblies of thepresent invention may comprise two or more materials to provide areliable seal (e.g., a water-tight seal) between the piston assembly andthe interior wall of the reservoir.

In one aspect, the present invention relates to an osmotic deliverysystem for delivery an active agent formulation to a fluid environment.The osmotic delivery system typically comprises a reservoir that definesa lumen, wherein the reservoir contains within the lumen the activeagent formulation and an osmotic agent formulation. A piston assembly istypically positioned in the lumen to isolate the active agentformulation from the osmotic agent formulation. Typically the pistonassembly provides a reliable seal between the piston assembly and theinterior wall of the reservoir. The piston assembly, for example,comprises a body constructed and arranged for positioning in the lumenand typically the body is made of a polymeric material that is resistantto leaching in an organic solvent. The body can further comprise meansfor engaging and sealing against a wall of the reservoir. The piston maybe movable within the reservoir in response to pressure within thereservoir. In some embodiments, the osmotic delivery system may beimplantable in a subject. The reservoir can be made, for example, froman impermeable material (e.g., a titanium alloy).

The piston assembly can comprise, for example, a body constructed andarranged for positioning in the lumen. In one embodiment of the currentinvention, the piston assembly can include, for example, a columnar bodycomprising a rim at a distal end thereof for engaging and sealingagainst the wall of the reservoir, and a spring (e.g., a radial spring,such as a canted coil spring) retained at the distal end for biasing therim against the wall of the reservoir. The spring may be, for example,made of a non-reactive metal. The spring may be retained in a cavity atthe distal end of the columnar body. Such a columnar body may compriseone or more rims at a distal end and/or placed at other locations alongthe length of the columnar body, wherein the rim engages and sealsagainst the interior wall of the reservoir, for example, by use of aretained spring.

In another embodiment, the body of the piston assembly can be made of apolymeric material that is resistant to leaching in an organic solventand can comprise one or more concentric grooves, each groove formed toretain an elastomeric O-ring that provides the means for engaging andsealing against the wall of the reservoir. Such one or more concentricgrooves can be located at one or more distal end of the body and/orplaced at other locations along the length of the columnar body, whereinthe elastomeric O-ring engages and seals against the interior wall ofthe reservoir.

In preferred embodiments, the body of the piston assembly can be made ofa polymeric material that is resistant to leaching in an organicsolvent. Exemplary polymeric materials include, but are not limited to,polyethylene, polyaryletherketones and ultra high molecular weightpolyethylenes. The organic solvent is typically an organic solvent thatis parenterally acceptable for use in a subject. Examples of organicsolvents include, but are not limited to, lauryl alcohol, benzylbenzoate, benzyl alcohol, lauryl lactate, decanol, ethyl hexyl lactate,long chain (C₈ to C₂₄) aliphatic alcohols, esters, or mixtures thereof.Preferred organic solvents for use in the practice of the presentinvention are benzyl benzoate, benzyl alcohol, or mixtures thereof. Thepolymeric material preferably produces volatile leachates at aconcentration of less than about 1.4 μg/ml when exposed to the organicsolvent at 40° C. for at least about 45 days, more preferably for atleast about 90 days. The polymeric material preferably producesnon-volatile leachates at a concentration of less than about 9.0 μg/mlwhen exposed to the organic solvent at 40° C. for at least about 45days, more preferably for at least about 90 days.

In some embodiments, the osmotic delivery system can, for example,include a semipermeable membrane positioned at a first end of thereservoir adjacent the osmotic agent formulation. Further, a flowmodulator with an orifice for delivering the active agent formulation tothe fluid environment may, for example, be positioned at a second end ofthe reservoir adjacent the active agent formulation.

The active agent formulation of the osmotic delivery system can comprisea suspension formulation. Examples of suspension formulations include,but are not limited to, combinations of a particle formulation and asuspension vehicle. Particle formulations can comprise a selectedpeptide, for example, one or more interferon (e.g., alpha interferon,beta interferon, delta interferon, gamma interferon, omega interferon,lambda interferon, tau interferon, or mixtures thereof). In preferredembodiments, the interferon can be omega interferon or beta interferon.Further, the active agent formulation may comprise a suspensionformulation comprising a particle formulation comprising aninsulinotropic peptide (e.g., glucagon like protein 1 (GLP-1) orexendin-4). Preferred organic solvents for use in suspension vehiclesinclude, but are not limited to, benzyl benzoate, benzyl alcohol, ormixtures thereof.

In one embodiment of the osmotic delivery system of the presentinvention, the active agent formulation comprises a suspensionformulation comprising a particle formulation (e.g., comprising omegainterferon, sucrose, methionine, citric acid monohydrate, and sodiumcitrate) and a suspension vehicle (e.g., comprising, benzyl benzoate andpolyvinylpyrrolidone (PVP)). The osmotic agent formulation comprises twocylindrical tablets, each tablet comprising, for example, sodiumchloride salt with cellulosic and povidone binders. The piston assemblycomprises a columnar body comprising a rim at a distal end thereof forengaging and sealing against the wall of the reservoir and a springretained at the distal end for biasing the rim against the wall of thereservoir. The piston assembly comprises ultra-high molecular weightpolyethylene, and the spring is a canted coil spring. This embodimentmay further comprise (i) a semipermeable membrane (made of for example,polyurethane) positioned at a first end of the reservoir adjacent theosmotic agent formulation, and (ii) a flow modulator (made of, forexample, polyetheretherketone) positioned at a second end of thereservoir adjacent the active agent formulation. In addition, thisembodiment can be implantable in a subject.

Another aspect of this invention relates to a method of manufacturingthe osmotic delivery system, comprising the reservoir, the active agentformulation, the osmotic agent formulation, the piston assembly, asemipermeable membrane and a flow modulator. Steps of the method ofmanufacturing may include, for example, assembling the reservoir, theactive agent formulation, the osmotic agent formulation, the pistonassembly, the semipermeable membrane and the flow modulator, such thatthe piston assembly is positioned in the lumen to isolate the activeagent formulation from the osmotic agent formulation, the semipermeablemembrane is positioned at a first end of the reservoir adjacent theosmotic agent formulation, and the flow modulator is positioned at asecond end of the reservoir adjacent the active agent formulation.

One embodiment of the present invention relates to an osmotic deliverysystem for delivery an active agent formulation to a fluid environment.The osmotic delivery system comprises a reservoir (made, for example,from a titanium alloy) having a lumen that contains the active agentformulation and an osmotic agent formulation. The active agentformulation comprises a suspension formulation comprising (i) a particleformulation (e.g., comprising omega interferon, sucrose, methionine,citric acid monohydrate, and sodium citrate), and (ii) a suspensionvehicle (e.g., comprising, benzyl benzoate and polyvinylpyrrolidone(PVP)). The osmotic agent formulation comprises two cylindrical tablets,each tablet comprising, for example, sodium chloride salt withcellulosic and povidone binders. A piston assembly positioned in thelumen isolates the active agent formulation from the osmotic agentformulation, wherein (i) the piston assembly comprises a columnar bodyhaving an hour-glass-like shape constructed and arranged for positioningin the lumen, and (ii) the columnar body comprises ultra-high molecularweight polyethylene. Further the columnar body has a rim at a distal endthereof for engaging and sealing against a wall of the reservoir and acanted coil spring retained at the distal end for biasing the rimagainst the wall of the reservoir. This embodiment comprises asemipermeable membrane (made, for example, from polyurethane) positionedat a first end of the reservoir adjacent the osmotic agent formulation,as well as a flow modulator (made, for example, frompolyetheretherketone) that is positioned at a second end of thereservoir adjacent the active agent formulation.

A further aspect of the present invention relates to treatinginterferon-responsive diseases (e.g., multiple sclerosis or viralinfection, such as, HCV infection) with a method that comprisesadministering the devices described herein. Typically the osmoticdelivery system of the present invention is implanted in a subject toprovide delivery of the active agent (e.g., interferon) at atherapeutically effective rate. The interferon used may be, for example,alpha interferon, beta interferon, omega interferon, or combinationsthereof.

Another aspect of treatment relates to a method of treating diabetes ordiabetes-related diseases by administering the devices described herein.Typically the osmotic delivery system of the present invention isimplanted in a subject to provide delivery of the active agent (e.g.,insulinotropic peptide) at a therapeutically effective rate.

In yet another aspect, the present invention relates to a pistonassembly adapted for positioning in a lumen of a reservoir for anosmotic delivery system. The piston assembly typically comprises a bodyconstructed and arranged for positioning in the lumen. The body may bemade of a polymeric material that is resistant to leaching in thepresence of an organic solvent. Examples of such solvents include, butare not limited to benzyl benzoate and benzyl alcohol. The body furthercomprises a device or means for engaging and sealing against a wall ofthe reservoir.

In some embodiments, the body may be a columnar body comprising a deviceor means for engaging and sealing against a wall of the reservoir, forexample, wherein the device or means comprises a rim at a distal end ofthe columnar body for engaging and sealing against the wall of thereservoir, and a spring retained at the distal end for biasing the rimagainst the wall of the reservoir. The spring can be a canted coilspring made, for example, of a non-reactive metal.

In another embodiment, the piston assembly may comprise a bodycomprising one or more concentric grooves. Each groove may be formed toretain an elastomeric O-ring that provides the means for engaging andsealing against the wall of the reservoir.

Exemplary polymeric materials for the body of the piston assemblyinclude, but are not limited to, polyethylene, polyaryletherketones andultra high molecular weight polyethylenes. Preferably, the polymericmaterial produces volatile leachates at a concentration of less thanabout 1.4 μg/ml when exposed to the organic solvent at 40° C. for atleast about 45 days, more preferably for at least about 90 days.Preferably, the polymeric material produces non-volatile leachates at aconcentration of less than about 9.0 μg/ml when exposed to the organicsolvent at 40° C. for at least about 45 days, more preferably for atleast about 90 days.

These aspects and embodiments of the invention are described in detailwith reference to a few preferred embodiments, as illustrated, forexample, in the accompanying drawings. In describing some preferredembodiments herein below, numerous specific details are set forth inorder to provide a thorough understanding of the invention. However, itwill be apparent to one skilled in the art that the invention may bepracticed without some or all of these specific details. In otherinstances, well-known features and/or process steps have not beendescribed in detail so as not to unnecessarily obscure the invention. Inaddition, like or identical reference numerals are used to identifycommon or similar elements.

3.0.0 COMPONENTS OF AN EXEMPLARY OSMOTIC DELIVERY SYSTEM

FIG. 1 presents a cross-sectional view of an example of an osmoticdelivery system including a piston assembly.

FIG. 1 depicts an osmotic delivery system 100 having a reservoir 102with a lumen 104. A piston assembly 200 is positioned in the lumen 104.The piston assembly 200 divides the lumen 104 into two chambers 108,110. In one example, the chamber 108 contains an active agentformulation 112 and the chamber 110 contains an osmotic agentformulation 114. A semipermeable membrane 116 is positioned at a firstend 118 of the reservoir 102, adjacent the chamber 110 containing theosmotic agent formulation 114. A flow modulator 120 is positioned at asecond end 122 of the reservoir 102, adjacent the chamber 108 containingthe active agent formulation 112. The flow modulator 120 includes adelivery orifice 124. The flow modulator 120 may be any suitable flowdevice having a delivery orifice. Alternatively, the second end 122 ofthe reservoir 102 may be closed-ended and may include the deliveryorifice.

Fluid is imbibed into the chamber 110 through the semipermeable membrane116. The active agent formulation 112 is dispensed from the chamber 108through the delivery orifice 124 in the flow modulator 120. The pistonassembly 200 engages and seals against the wall 126 of the reservoir102, thereby isolating the osmotic agent formulation 114 and fluidimbibed through the semipermeable membrane 116 from the active agentformulation 112. At steady-state, the active agent formulation 112 isexpelled through the delivery orifice 124 in the flow modulator 120 at arate corresponding to the rate at which external fluid is imbibed intothe chamber 110 through the semipermeable membrane 116.

3.1.0 Piston Assembly

The piston assembly (e.g., 200, FIG. 1) is made, in a preferredembodiment, of a material that is substantially resistant to leaching byan organic solvent, for example, that is present in the active agentformulation (e.g., 112, FIG. 1). Resistance of the piston assembly to anorganic solvent means that there are minimal leachates and minimal or nodimensional changes, swelling, deformation and disintegration when thepiston assembly is exposed to the organic solvent. Examples of organicsolvents useful in the practice of the present invention include, butare not limited to, parenterally acceptable organic solvents, forexample, lauryl alcohol, benzyl benzoate, benzyl alcohol, lauryllactate, decanol (also called decyl alcohol), ethyl hexyl lactate, longchain (C₈ to C₂₄) aliphatic alcohols, esters, or mixtures thereof. Inone embodiment, the piston assembly 200 is made of a material that isresistant to leaching by benzyl benzoate. In another embodiment, thepiston assembly is made of a material that is resistant to leaching bybenzyl alcohol.

FIG. 2A depicts a cross-section of an example of a piston assembly. Thepiston assembly 200 comprises a body (e.g., a columnar body 202) thatdoes not allow flow there through. A first distal end 203 of thecolumnar body 202 includes an inner ridge 204 and an outer rim 206arranged concentrically. A cavity 208 is formed between the ridge 204and rim 206. The cavity 208 is substantially annular in shape and may becontinuous or segmented. At least one spring 210 is positioned in thecavity 208.

The spring 210 applies a radial force on the rim 206, biasing the rim206 outwardly. Preferably, the radial force is uniformly applied aboutthe circumference of the rim 206. In one example, the spring 210 is acanted coiled spring such as available from Bal Seal Engineering(Foothill Ranch, Calif.). A canted coil spring may be described as around-wire spring with inclining (i.e., canted), elliptical coils. Thecoils deflect independently when compressed. The entire spring respondswhenever any portion of a coil is deflected, permitting uniform appliedradial force at each contact point of the coil spring with a surface.Canted-coil springs have been previously described (see, e.g., U.S. Pat.Nos. 4,655,462; 4,826,144; 4,830,344; 4,876,781; 4,893,795; 4,907,788;4,915,366; 4,934,666; 4,961,253; 4,964,204; 4,974,821; 5,072,070;5,079,388; 5,108,078; 5,117,066; 5,134,244; 5,160,122; 5,161,806; and5,203,849). However, the invention is not limited to use of a cantedcoil spring. Any spring (e.g., radial spring) or spring-like meanscapable of exerting a radial force on the rim 206 such that the rim 206is biased outwardly may be positioned in the cavity 208.

When the piston 200 is positioned in the lumen (104 in FIG. 1), thespring 210 biases the rim 206 against the interior wall (126 in FIG. 1)of the reservoir (102 in FIG. 1), thereby maintaining a seal between therim 206 and the interior wall of the reservoir. The spring 210 providesa substantially constant sealing force over long periods of time, evenwhen the material of the columnar body 202 creeps over time. The forceof the spring 210 can be selected such that a seal is maintained betweenthe piston assembly 200 and the interior wall of the reservoir duringoperation of the osmotic delivery system (100 in FIG. 1). The ridge 204may include a lip 212 that partially encloses or partially covers thecavity 208 such that the lip serves to help retain the spring 210 in thecavity 208.

In another example of the piston 200, as illustrated in FIG. 2B, asecond distal end 216 of the columnar body 202, opposite the firstdistal end 203, may also include a rim 206, cavity 208, and ridge 204,and other features as described above for the first distal end 203(e.g., a lip 212).

The outer surface 218 of the columnar body 202 may be smooth, asillustrated in FIG. 2A. Alternately, as illustrated in FIG. 2B,undercuts 220 and/or ribs 222 may be formed on the outer surface 218 ofthe columnar body 202 to further enhance the seal between the columnarbody 202 and the interior wall (126 in FIG. 1) of the reservoir (102 inFIG. 1) when the piston assembly 200 is positioned in the lumen (104 inFIG. 1) of the reservoir. The cross-sectional shape of the columnar body202 may be the same or vary along the length of the columnar body 202.For example, where undercuts 220 are formed on the columnar body 202,the cross-sectional shape of the undercut sections 220 may differ fromthe cross-sectional shape of the rib sections 222. The cross-sectionalshape of the columnar body 202 may be circular, elliptical, or any othersuitable shape. Preferably, the outer (circumferential) profile of therim 206 conforms to the inner (circumferential) profile of the lumen ofthe reservoir. Therefore, where the lumen has a circular profile, therim 206 will also preferably have a circular profile. Preferably, theouter diameter of the rim 206 is selected such that the rim 206 engagesthe wall of the reservoir when inserted in the lumen to prevent, forexample, flow-through between the chamber 108 in FIG. 1, which comprisesan active agent formulation 112 (in FIG. 1), and the chamber 110 in FIG.1, which comprises an osmotic agent formulation 114 (in FIG. 1).

The columnar body 202 is preferably made of a polymeric material that issubstantially impermeable to and substantially resistant to leachingwhen exposed to an organic solvent, for example, an organic solvent usedin the formulation of a suspension vehicle. In one embodiment, apolymeric material that is suitable for the columnar body 202 producesvolatile and non-volatile leachates less than about 1.4 μg/ml and lessthan about 9 μg/ml, respectively, when exposed to an organic solvent at40° C. for about 45 days, and for about 90 days. Preferably minimalleachates occur during the course of storage and usage such that theintegrity and performance of the piston assembly is not substantially,adversely affected for the intended period of storage and use. Theamount of acceptable leachates can be determined depending on, forexample, the toxicity of the leachate and other factors including, butnot limited to, the following: daily dose of leachates; route ofadministration (e.g., oral, inhaled, injected, or delivered from animplanted device); clinical vs. commercial use; and reactivity orinterference of leachates with active agent, other device components,packaging, assays or functionality of the osmotic delivery system. Inone embodiment, the polymeric material used for the columnar body 202 isresistant to leaching in the presence of an organic solvent selectedfrom, but not limited to, the group including lauryl alcohol, benzylbenzoate, benzyl alcohol, lauryl lactate, decanol (also called decylalcohol), ethyl hexyl lactate, and long chain (C₈ to C₂₄) aliphaticalcohols, esters, or mixtures thereof. In a preferred embodiment, thepolymeric material used for the body of the piston assembly (e.g.,columnar body 202, FIG. 1) is resistant to leaching in the presence ofbenzyl benzoate and/or benzyl alcohol.

In one embodiment of the present invention, the body of the pistonassembly is similar to the shape presented in FIG. 2B, that is columnar,but with more of an hour-glass shape (i.e. only in contact with theinner surface of the lumen near distal ends of the piston). In generalthe body of the piston is columnar (i.e., column-like) though one ofskill in the art, in view of the teachings of the specification, canchoose other shapes effective to prevent, for example, flow-throughbetween the chamber 108 in FIG. 1, which comprises an active agentformulation 112 (in FIG. 1), and the chamber 110 in FIG. 1, whichcomprises an osmotic agent formulation 114 (in FIG. 1). The core of thepiston assembly may be an ultra-high molecular weight polyethylene andthe canted coil spring may be made of titanium alloy. The body of thepiston assembly can take any form such that at least a portion of theassembly contacts the inner surface of the lumen to provide substantialseparation between the contents of the active agent chamber and contentsof the osmotic agent chamber of the lumen of the reservoir.

Examples of polymeric materials suitable for making the body of thepiston assembly include, but are not limited to, the following:polyethylene; polyaryletherketones (e.g., polyetherketone andpolyetheretherketone (PEEK)); and ultra-high-molecular-weightpolyethylene. Other examples of useful polymers include, but are notlimited to, the following: perfluoronated elastomers and polymers (e.g.elastomeric materials having broad chemical resistance, combining theresilience and sealing force of an elastomer with chemical resistanceapproaching that of polytetrafluoroethylene (PTFE) as available, forexample, CHEMRAZ® (Greene, Tweed of Delaware, Inc., Wilmington Del.)materials); polyimides; and polysulfones. In a preferred embodiment thepolymeric material has some natural lubricity relative to the materialcomprising the inner wall of the lumen. The polymeric material may beone that adheres to the wall of the reservoir upon wetting. The spring210 retained on the columnar body 202 may be made of a metallicmaterial. Preferably, the metallic material is non-reactive (or inert)and biocompatible. Materials used for the spring 210 may be similar tothe materials used for the reservoir (102 in FIG. 1) of the osmoticdelivery system, as will be further described below. Alternatively,other means to provide a seal (e.g., a water-tight seal) between thepiston and the interior wall of the lumen may be employed, some of whichare discussed further herein below.

In addition to use of a solid core of the polymeric materials to makethe piston assembly, a thick impermeable coating of one or more of thesesolvent resistant polymers on a dissimilar core substrate may be used.

Furthermore, although an exemplary shape of the piston is described as acylinder, the shape of the piston assembly may vary from a cylindricalshape (e.g., the piston may have an hour glass shape that contacts withthe inner surface of the lumen near the distal ends). Shape of thepiston assembly is typically such that it contacts the inner surface ofthe lumen to (i) provide separation between the active agent chamber andthe osmotic agent chamber of the lumen, and (ii) prevent flow-throughthere between. In preferred embodiments, the piston assemblysubstantially prevents fluid exchange between the active agent chamberand the osmotic agent chamber of the lumen.

In one aspect, the piston assembly of the present invention may comprisetwo or more components or materials, wherein the piston effectivelyseparates the active drug formulation from the osmotic engine. By usingmultiple materials or multiple components to construct a piston, eachmaterial or component may be selected to provide one or more advantages.For example, thermoplastics such as polyethylene (e.g., ultra highmolecular weight polyethylene (UHMWPE)) and polyetheretherketone (PEEK)have a broad resistance to chemicals typically used in pharmaceuticalapplications; however, such thermoplastics typically do not have elasticproperties needed to create a tight seal against the inner wall of thereservoir. However, if one or more rim/spring, spring, O-ring, gasket,seal, packing, or the like sealing means, is used with the thermoplasticmaterial or component of the piston assembly, an acceptable seal againstthe inner wall of the reservoir is created. Embodiments using cantedcoil springs are described herein above.

Elastomers, for example, perfluoroelastomer, typically have broadchemical resistance but can be difficult and costly to mold into aone-piece piston. However, a thin, perfluoroelastomer O-ring, gasket, orcoating may be installed on to or applied to on a rigid core material(e.g., thermoplastic, ceramic, metal) to create an acceptable pistonseal. Such combination (or composite) pistons may help solve someproblems typically associated with use of single materials or singlecomponent piston. For example, although some single materials have abroad resistance to chemicals that can be used in pharmaceuticalapplications, when used to create single material pistons they typicallydo not have elastic properties needed to create a tight seal against theinner wall of the reservoir. Also, some elastomers that are useful forcreating tight seals against the inner wall of the reservoir are veryexpensive (e.g., perfluoroelastomer) and difficult to mold into acomplete piston. As discussed herein, O-rings or the like can be formedfrom such elastomers thus avoiding the need to mold complete pistonsfrom the elastomer and reducing production cost as well. Accordingly,the piston assemblies of the present invention may comprise two or morecomponents and/or two or more materials, thus providing broader chemicalcompatibility with excipients, vehicles, osmotic systems, and drugsubstances.

Accordingly, in one aspect the present invention relates to a pistonassembly or seal in a drug delivery device that is used to separate twoor more fluids. The piston assembly or seal may be made from two or morematerials and/or components that provide superior utility to a pistonassembly made from a single material or component in the areas of, butnot limited to: chemical compatibility, biocompatibility, cost,strength, system start-up, resistance to compression set (shelfstability), and part complexity. Composite piston assemblies can becleaned, lubricated, and installed in the same or similar manner to asingle component or single material pistons.

One embodiment of the present invention includes a thermoplastic corepiece with a cavity that contains a canted metallic spring that suppliesa sealing force to a thin flange or lip of the thermoplastic core, asshown in FIG. 2A and FIG. 2B. This type of design may incorporatemultiple spring seals and be installed with either end contacting thedrug formulation. The thermoplastic core has excellent chemical andbiological compatibility, strength and (being incompressible) providesexcellent system start-up delivery. This embodiment is described in moredetail herein above.

Another aspect of the present invention includes a core (e.g., athermoplastic core) with one or more concentric furrows, grooves orglands (i.e., a gland is a groove void) that accepts an elastomericO-ring or gasket. The O-ring or gasket provides the seal with the innerwall of the lumen of the reservoir. Two examples of such pistonassemblies are shown in FIG. 4A, FIG. 4B and FIG. 4C. Referring to FIG.4A, two elastomeric O-rings 402 and 404 are shown. The body of thepiston assembly 400 is, for example, a thermoplastic (e.g., PEEK orUHMWPE) or titanium alloy core. The O-rings 402 and 404 may be made ofthe same or different materials. In one embodiment, the O-ring thatforms a seal relative to the reservoir chamber comprising an organicsolvent may be made of a material resistant to damage or degredation bythe solvent. For example, O-ring 402 may be made of aperfluoroelastomer. The second O-ring 404 that forms a seal relative tothe reservoir chamber comprising the osmotic agent may be made of adifferent material, for example, a fluoroelastomer or other elastomer.FIG. 4B presents a schematic view of the piston assembly shown in FIG.4A. In addition to the O-rings 402 and 404, and the body 400, FIG. 4Billustrates the groove or gland 406 formed by the body of the pistonassembly into which the O-rings are seated.

Another piston assembly with multiple O-rings is illustrated in FIG. 4C.In FIG. 4C, three O-rings 402 and 404 are shown. As described above,these O-rings may all be made of the same or similar material, or theO-rings may be made of a variety of materials. For example, in oneembodiment, the O-ring that forms a seal relative to the reservoirchamber comprising an organic solvent may be made of a materialresistant to damage or degredation by the solvent. For example, O-ring402 may be made of a perfluoroelastomer. The second and third O-rings404 that form a seal relative to the reservoir chamber comprising theosmotic agent may be made of a different material, for example, afluoroelastomer or other elastomer. The body of the piston assembly 400may be made of a variety of materials as described herein and may alsoassume a number of suitable shapes including, but not limited to, asubstantially columnar body.

A thermoplastic core may provide excellent chemical and biologicalcompatibility and (being incompressible) also provide excellent systemstart-up delivery. The elastomeric O-rings or gaskets can be small tokeep cost low (e.g., perfluoroelastomer) or different compositionO-rings or gaskets may be used on the same piston if the fluids beingseparated have different solvating powers (e.g., saturated salt solutionversus an organic solvent drug suspension). The elastomeric seals canbe, for example, separate components installed into the glands, or theymay be attached to the thermoplastic core by an over-molding or bondingprocess.

One embodiment of the present invention is the ability to control theamount of leachates produced from the piston assembly by carefulselection of materials for making the piston assembly in view of organicsolvent components that contact the piston assembly. In otherembodiments, the piston assemblies of the present invention are usefulwith a wide variety of pharmaceutical excipients and provide severalgeneral advantages over previously used piston assemblies. For example,the use of two or more materials can be used to provide a reliable seal(e.g., a water-tight seal) between the piston assembly and the interiorwall of the reservoir, and the use of two or more materials can provideeasier manufacturing of the piston assembly and can provide cost savingsas well. Further, the piston assemblies of the present invention provideacceptable operation of the piston and the osmotic delivery system forlong periods of time, for example, greater than about 45 days,preferably greater than about 90 days, more preferably greater thanabout 180 days, more preferably greater than about 365 days. Inaddition, the piston assemblies of the present invention producepharmaceutically acceptably low levels or less of volatile andnon-volatile leachates when used in combination with organic solvents.

The piston assemblies described herein may be used, for example, inosmotic delivery systems such as the DUROS® (ALZA Corporation, Palo AltoCalif.) delivery system or similar system (see, e.g., U.S. Pat. Nos.5,728,396; 5,985,305; 5,997,527; 6,113,938; 6,132,420; 6,156,331;6,217,906; 6,261,584; 6,270,787; 6,287,295; 6,395,292; 6,508,808;6,544,252; 6,635,268; 6,682,522; 6,923,800; 6,939,556; 6,976,981;6,997,922; 7,014,636; 7,112,335; 7,163,688).

The DUROS® device releases an active agent at a predetermined rate basedon the principle of osmosis. Extracellular fluid (e.g., from the fluidenvironment into which the device was placed, for example, byimplantation in a subject) enters the DUROS® device through asemi-permeable membrane directly into a salt engine that expands todrive the piston at a slow and even delivery rate. Movement of thepiston forces the drug formulation to be released through the orifice orexit port.

Implantable devices, for example, the DUROS® device, provide thefollowing advantages for administration of a suspension formulations:true zero-order release of the active agent pharmacokinetically;long-term release period time (e.g., up to about 12 months); andreliable delivery and dosing of the active agent.

3.2.0 Semipermeable Membrane

The reservoir (e.g., 102, FIG. 1) may be sized such that it can beimplanted within a body. The first end (e.g., 118, FIG. 1) may be open,and the semipermeable membrane (e.g., 116, FIG. 1) may be provided as aplug which is inserted in the open end (e.g, 118, FIG. 1). Such a plugmay be, for example, inserted by press-fitting or usingscrew/thread-like means. Alternately, the semipermeable membrane (e.g.,116, FIG. 1) may be integral with the end (e.g., 118, FIG. 1) of thereservoir (e.g., 102, FIG. 1).

In one embodiment of the semipermeable membrane as a plug, thesemipermeable membrane 116 may include an enlarged portion 116 a thatacts as a stop member engaging the first end 118 of the reservoir 102.The outer surface 116 b of the semipermeable membrane 116 may have ribs116 c that engage the wall 126 of the reservoir 102, thereby locking thesemipermeable membrane 116 to the reservoir 102 and allowing a seal tobe formed between the reservoir 102 and the semipermeable membrane 116.The wall 126 of the reservoir 102 may also include undercuts that engagethe ribs 116 c on the semipermeable membrane 116. The semipermeablemembrane 116 acts as a one-way valve, allowing flow into the chamber 110from an external fluid environment while preventing flow out of thechamber 110 to the external fluid environment.

Semipermeable materials suitable for the semipermeable membrane (e.g.,116, FIG. 1) are those that can conform to the shape of the lumen (e.g.,104, FIG. 1) of the reservoir (e.g., 102, FIG. 1) upon wetting.Preferably, these materials can also adhere to the wall (e.g., 126,FIG. 1) of the reservoir (e.g., 102, FIG. 1) upon wetting, therebyproviding or maintaining a seal between the wall (e.g., 126, FIG. 1) andthe semipermeable membrane (e.g., 116, FIG. 1). Typically, thesesemipermeable materials are polymeric materials, which can be selectedbased on the permeability of the membrane and system configurationrequirements. Examples of suitable semipermeable materials include, butare not limited to, plasticized cellulosic materials; enhancedpolymethyl methacrylates (PMMAs) such as hydroxyethylmethacrylate(HEMA); and elastomeric materials such as polyurethanes and polyamides,polyether-polyamind copolymers, thermoplastic copolyesters; and thelike.

Generally the membrane permeability ranges of the polymeric material isselected in order to provide the appropriate influx of aqueous solutioninto the lumen of the osmotic delivery system such that the osmoticagent expands at a rate determined to provide delivery of an activeagent at a desired rate for a selected period of time. Table 1 presentsexamples of water permeability ranges for membranes for a 150 μl nominalvolume osmotic delivery system.

TABLE 1 System duration [months] 1 3 6 12 Water Permeability 4.5-5.51.4-1.7 0.8-0.9 0.37-0.40 [μl/day]

The semipermeable membrane material is typically selected based on, forexample, the equilibrium water absorption percent of the polymericmaterial and/or the polymeric material's dynamic water permeabilityrate.

In one embodiment of the present invention, the semipermeable membraneis an aliphatic, polyether-based polyurethane having a nominalequilibrium water absorption of 33%. The thermoplastic polyurethane maybe injection molded to form a membrane with four barbed, concentric ribsand an enlarged portion (e.g., 116 a, FIG. 1) that acts as a stopmember.

3.3.0 Osmotic Agent

The osmotic agent (or water-swellable agent) formulation (e.g., inchamber 110, FIG. 1) is preferably a tissue tolerable formulation whosehigh osmotic pressure and high solubility propels the active agent overa long period of time while remaining in saturated solution in the wateradmitted by the semipermeable membrane. The osmotic agent is preferablyselected for tolerability by subcutaneous tissue, at least at pumpingrates and hypothetically resulting concentrations to allow inadvertentdispensing from implanted devices left in the patient for a longer thanthe labeled period. In preferred embodiments, the osmotic agent does notdiffuse or permeate through the piston assembly to any appreciableamount (e.g., less than about 10%, more preferably less than about 8%,more preferably less than about 6%) under normal operating conditions.

The osmotic agent formulation may be, for example, in the form oftablets as shown in 114, FIG. 1. One or more such tablets may be used.Alternatively, the osmotic agent formulation may have other shape,texture, density, or consistency. For example, the osmotic agentformulation may be a slurry, a tablet, a molded or extruded material, apowder or granular form, or other form known in the art. The osmoticagent formulation may include one or more osmotic polymers. An osmoticpolymer is a hydrophilic polymer that can imbibe aqueous fluids (such asbiological fluids and water) and upon imbibing aqueous fluids expands toan equilibrium state and retains a significant portion of the imbibedfluid. An osmotic polymer can expand to a very high degree, for example,about 2 to about 50 times its initial volume. An osmotic polymer may ormay not be cross-linked. Preferred osmotic polymers are hydrophilicpolymers that are lightly cross-linked, such cross-links being formed bycovalent or ionic bonds or residue crystalline regions after swelling.Osmotic polymers may be, for example, of plant, animal or syntheticorigin.

Examples of osmotic polymers suitable for use in the osmotic agentformulation (e.g., 114, FIG. 1) include, but are not limited to, poly(hydroxy-alkyl methacrylate) having a molecular weight of from 30,000 to5,000,000; polyvinylpyrrolidone (PVP) having a molecular weight of from10,000 to 360,000; anionic and cationic hydrogels; polyelectrolytescomplexes; polyvinyl alcohol having a low acetate residual, cross-linkedwith glyoxal, formaldehyde, or glutaraldehyde and having a degree ofpolymerization of from 200 to 30,000; a mixture of methyl cellulose,cross-linked agar and carboxymethyl cellulose; a mixture ofhydroxypropyl methylcellulose and sodium carboxymethylcellulose; amixture of hydroxypropyl ethylcellulose and sodium carboxymethylcellulose; sodium carboxymethylcellulose; potassiumcarboxymethylcellulose; a water insoluble, water swellable copolymerformed from a dispersion of finely divided copolymer of maleic anhydridewith styrene, ethylene, propylene, butylene or isobutylene cross-linkedwith from 0.001 to about 0.5 moles of saturated cross-linking agent permole of maleic anhydride per copolymer; water swellable polymers ofN-vinyl lactams; polyoxyethylene-polyoxypropylene gel;polyoxybutylene-polyethylene block copolymer gel; carob gum; polyacrylicgel; polyester gel; polyuria gel; polyether gel; polyamide gel;polypeptide gels; polyamino acid gels; polycellulosic gel; polygum gel;and initially dry hydrogels that imbibe and absorb water that penetratesthe glassy hydrogel and lowers its glass temperature.

Other examples of osmotic polymers include, but are not limited to, thefollowing: polymers that form hydrogels such as CARBOPOL® (Noveon, Inc.,Cleveland Ohio), acidic carboxypolymer, a polymer of acrylic andcross-linked with a polyallyl sucrose, also known ascarboxypolymethylene and carboxyvinyl polymer having a molecular weightof 250,000 to 4,000,000; cynamer polyacrylamides; cross-linked waterswellable indene-maleic anhydride polymers; GOOD-RITE® (Noveon, Inc.,Cleveland Ohio) polyacrylic acid having a molecular weight of 80,000 to200,000; POLYOX® (Union Carbide Chemicals & Plastics TechnologyCorporation, Danbury Conn.) polyethylene oxide polymer having amolecular weight of 100,000 to 5,000,000 and higher; starch graftcopolymers; acrylate polymer polysaccharides composed of condensedglucose units such as diester cross-linked polygluran; and the like.

The osmotic agent formulation may include an osmotic effective soluteeither in addition to or in lieu of the osmotic polymer described above.Osmotic effective solutes include inorganic and organic compounds thatcan exhibit an osmotic pressure gradient across the semipermeablemembrane when the osmotic delivery system is placed in a fluidenvironment. An osmotic effective solute in the osmotic agentformulation (e.g., 114, FIG. 1) imbibes fluid into the chamber (e.g.,110, FIG. 1) through the semipermeable membrane (e.g., 116, FIG. 1),thereby making available fluid pressure to displace the piston assembly(e.g., 200, FIG. 1) and push the active agent formulation (e.g., 112,FIG. 1) through the delivery orifice (e.g., 124, FIG. 1) via the flowmodulator (e.g., 120, FIG. 1). Osmotic effective solutes or osmagents(i.e., the non-volatile species that are soluble in water and create theosmotic gradient driving the osmotic inflow of water) useful in theosmotic agent formulation include, but are not limited to, magnesiumsulfate, magnesium chloride, sodium chloride, potassium sulfate, sodiumsulfate, lithium sulfate, sodium phosphate, potassium phosphate,d-mannitol, urea, inositol, magnesium succinate, tartaric acid,inositol, carbohydrates, and various monosaccharides, oligosaccharidesand polysaccharides such as sucrose, glucose, lactose, fructose,raffinose and dextran, as well as mixtures of any of these variousspecies.

Osmotic agents such as sodium chloride (NaCl) with appropriatetabletting agents (lubricants and binders; e.g., cellulosic and povidonebinders) and viscosity modifying agents, such as sodiumcarboxymethylcellulose or sodium polyacrylate are examples of preferredosmotic agents. Other osmotic agents useful as the water-swellable agentinclude osmopolymers and osmagents and are described, for example, inU.S. Pat. No. 5,413,572. A liquid or gel additive or filler may be addedto chamber 20 to exclude air from spaces around the osmotic engine.Exclusion of air from the devices generally means that delivery rateswill be less affected by nominal external pressure changes (e.g., about+/−7 p.s.i. (+/−5 a.t.m.)).

An osmotic tablet is an osmotic agent that is a fluid-attracting agentused to drive the flow of the active agent. The osmotic agent may be anosmagent, an osmopolymer, or a mixture of the two. Species which fallwithin the category of osmagent (i.e., the non-volatile species whichare soluble in water and create the osmotic gradient driving the osmoticinflow of water) vary widely. Examples of such osmagents are well knownin the art and include those listed herein above. The osmotic agent 114in FIG. 1 is illustrated as osmotic tablets. Osmotic tablets may, forexample, comprise sodium chloride, sodium carboxymethylcellulose,polyvinylpyrrolidone (PVP), magnesium stearate, and water for injection.

The osmotic agent may be manufactured by a variety of techniques, manyof which are known in the art (see, e.g., U.S. Pat. Nos. 6,923,800 and6,287,295). In one such technique, an osmotically active agent isprepared as solid or semi-solid formulations and pressed into pellets ortablets whose dimensions correspond to slightly less than the internaldimensions of the respective chambers that they will occupy in theenclosure interior. Depending on the nature of the materials used, theagent and other solid ingredients that may be included may be processedprior to the formation of the pellets by such procedures asball-milling, calendaring, stirring or roll-milling to achieve a fineparticle size and fairly uniform mixtures of each ingredient. Theenclosure for pressing the osmotic agent into tablets or pellets may beformed from a wall-forming material by the use of a mold, with thematerials applied either over the mold or inside the mold, depending onthe mold configuration.

3.4.0 Active Agent

The active agent formulation (e.g., 112, FIG. 1) may comprise one ormore active agents. The active agent may be any physiologically orpharmacologically active substance, particularly those known to bedelivered to the body of a human or an animal such as medicaments,vitamins, nutrients, or the like. Active agents that may be delivered bythe osmotic delivery system of the present invention include, but arenot limited to, drugs that act on the peripheral nerves, adrenergicreceptors, cholinergic receptors, the skeletal muscles, thecardiovascular system, smooth muscles, the blood circulatory system,synoptic sites, neuroeffector junctional sites, endocrine and hormonesystems, the immunological system, the reproductive system, the skeletalsystem, autacoid systems, the alimentary and excretory systems, thehistamine system or the central nervous system. Further, active agentsthat may be delivered by the osmotic delivery system of the presentinvention include, but are not limited to, active agents used for thetreatment of infectious diseases, chronic pain, diabetes, auto-immunedisorders, endocrine disorders, metabolic disorders, and rheumatologicdisorders.

Suitable active agents include, but are not limited to, the following:peptides, proteins, polypeptides (e.g., enzymes, hormones, cytokines),polynucleotides, nucleoproteins, polysaccharides, glycoproteins,lipoproteins, steroids, analgesics, local anesthetics, antibioticagents, anti-inflammatory corticosteroids, ocular drugs, other smallmolecules for pharmaceutical use (e.g., ribavirin), or synthetic analogsof these species, as well as mixtures thereof. Preferred active agentsinclude macromolecules (e.g., peptides, proteins and polypeptides) oractive agents that are highly potent.

The osmotic devices of the invention may be used to deliver a widevariety of active agents. These agents include, but are not limited to,pharmacologically active peptides proteins, polypeptides, genes, geneproducts, other gene therapy agents, or other small molecules. Thepolypeptides may include but are not limited to the following: growthhormone; somatostatin; somatropin, somatotropin, somatotropin analogues,somatomedin-C, somatotropin plus an amino acid, somatotropin plus aprotein; follicle stimulating hormone; luteinizing hormone, luteinizinghormone-releasing hormone (LHRH), LHRH analogues such as leuprolide,nafarelin and goserelin, LHRH agonists or antagonists; growth hormonereleasing factor; calcitonin; colchicine; gonadotropic releasinghormone; gonadotropins such as chorionic gonadotropin; oxytocin,octreotide; vasopressin; adrenocorticotrophic hormone; epidermal growthfactor; fibroblast growth factor; platelet-derived growth factor;transforming growth factor; nerve growth factor; prolactin; cosyntropin;lypressin polypeptides such as thyrotropin releasing hormone; thyroidstimulation hormone; secretin; pancreozymin; enkephalin; glucagon;endocrine agents secreted internally and distributed by way of thebloodstream; or the like.

Further active agents that may be delivered include but are not limitedto the following: alpha antitrypsin; factor VII; factor IX and othercoagulation factors; insulin; peptide hormones; adrenal corticalstimulating hormone, thyroid stimulating hormone and other pituitaryhormones; erythropoietin; growth factors such as granulocyte-colonystimulating factor, granulocyte-macrophage colony stimulating factor,insulin-like growth factor 1; tissue plasminogen activator; CD4;1-deamino-8-D-arginine vasopressin; interleukin-1 receptor antagonist;tumor necrosis factor, tumor necrosis factor receptor; tumor suppresserproteins; pancreatic enzymes; lactase; cytokines, including lymphokines,chemokines or interleukins such as interleukin-1, interleukin-2;cytotaxic proteins; superoxide dismutase; endocrine agents secretedinternally and distributed in an animal by way of the bloodstream;recombinant antibodies, antibody fragments, humanized antibodies, singlechain antibodies, monoclonal antibodies; avimers; or the like.

Further, the active agents that may be administered include inorganicand organic compounds without limitation including those compounds thattransport across a vessel. Examples of active agents that may be used inthe practice of the present invention include, but are not limited to,the following: hypnotics and sedatives such as pentobarbital sodium,phenobarbital, secobarbital, thiopental, amides and ureas exemplified bydiethylisovaleramide and alpha-bromo-isovaleryl urea, urethanes, ordisulfanes; heterocyclic hypnotics such as dioxopiperidines, andglutarimides; antidepressants such as isocarboxazid, nialamide,phenelzine, imipramine, tranylcypromine, pargyline); tranquilizers suchas chloropromazine, promazine, fluphenazine reserpine, deserpidine,meprobamate, benzodiazepines such as chlordiazepoxide; anticonvulsantssuch as primidone, diphenylhydantoin, ethltoin, pheneturide,ethosuximide; muscle relaxants and anti-parkinson agents such asmephenesin, methocarbomal, trihexylphenidyl, biperiden, levo-dopa, alsoknown as L-dopa and L-beta-3-4-dihydroxyphenylalanine; analgesics suchas morphine, codeine, meperidine, nalorphine; antipyretics andanti-inflammatory agents such as aspirin, salicylamide, sodiumsalicylamide, naproxin, ibuprofen; local anesthetics such as procaine,lidocaine, naepaine, piperocaine, tetracaine, dibucane; antispasmodicsand antiulcer agents such as atropine, scopolamine, methscopolamine,oxyphenonium, papaverine, prostaglandins such as PGE₁, PGE₂,PGF_(1alpha), PGF_(2alpha), PGA; anti-microbials such as penicillin,tetracycline, oxytetracycline, chlorotetracycline, chloramphenicol,sulfonamides, tetracycline, bacitracin, chlorotetracycline,erythromycin; anti-malarials such as 4-aminoquinolines,8-aminoquinolines and pyrimethamine; hormonal agents such asprednisolone, cortisone, cortisol and triamcinolone, androgenic steroids(for example, methyltestosterone, fluoxmesterone), estrogenic steroids(for example, 17-beta-estradoil and thinyl estradiol), progestationalsteroids (for example, 17-alpha-hydroxyprogesterone acetate,19-nor-progesterone, norethindrone); sympathomimetic drugs such asepinephrine, amphetamine, ephedrine, norepinephrine; cardiovasculardrugs such as procainamide, amyl nitrate, nitroglycerin, dipyridamole,sodium nitrate, mannitol nitrate; diuretics such as acetazolamide,chlorothiazide, flumethiazide; antiparasitic agents such as bepheniumhydroxynaphthoate, dichlorophen, enitabas, dapsone; neoplastic agentssuch as mechloroethamine, uracil mustard, 5-fluorouracil, 6-thioguanineand procarbazine; hypoglycemic drugs such as insulin related compounds(for example, isophane insulin suspension, protamine zinc insulinsuspension, globin zinc insulin, extended insulin zinc suspension)tolbutamide, acetohexamide, tolazamide, chlorpropamide; nutritionalagents such as vitamins, essential amino acids, and essential fats; eyedrugs such as pilocarpine base, pilocarpine hydrochloride, pilocarpinenitrate; antiviral drugs such as disoproxil fumarate, aciclovir,cidofovir, docosanol, famciclovir, fomivirsen, foscarnet, ganciclovir,idoxuridine, penciclovir, trifluridine, tromantadine, valaciclovir,valganciclovir, vidarabine, amantadine, arbidol, oseltamivir, peramivir,rimantadine, zanamivir, abacavir, didanosine, emtricitabine, lamivudine,stavudine, zalcitabine, zidovudine, tenofovir, efavirenz, delavirdine,nevirapine, loviride, amprenavir, atazanavir, darunavir, fosamprenavir,indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir,enfuvirtide, adefovir, fomivirsen, imiquimod, inosine, podophyllotoxin,ribavirin, viramidine, fusion blockers specifically targeting viralsurface proteins or viral receptors (for example, gp-41 inhibitor(T-20), CCR-5 inhibitor); anti-nausea such as scopolamine,dimenhydrinate); iodoxuridine, hydrocortisone, eserine, phospholine,iodide, as well as other beneficial active agents.

Numerous peptides, proteins, or polypeptides that are useful in thepractice of the present invention are described herein. In addition tothe peptides, proteins, or polypeptides described, modifications ofthese peptides, proteins, or polypeptides are also known to one of skillin the art and can be used in the practice of the present inventionfollowing the guidance presented herein. Such modifications include, butare not limited to, amino acid analogs, amino acid mimetics, analogpolypeptides, or derivative polypeptides. Further, the active agentsdisclosed herein may be formulated singly or in combination (e.g.,mixtures).

Some embodiments of the present invention comprise use of interferonpeptides (e.g., alpha, beta, delta, gamma, lambda, omega, tauinterferon, as well as analogs or derivatives thereof such as pegylatedforms; see, for example, The Interferons: Characterization andApplication, by Anthony Meager (Editor), Wiley-VCH (May 1, 2006)) orpeptide hormones for the treatment of diabetes and diabetes relatedconditions (e.g., insulinotropic peptides such as glucagon like protein(such as GLP-1), as well as analogues and derivatives thereof, orexendins (such as exendin-4), as well as analogs and derivativesthereof).

GLP-1 (including three forms of the peptide, GLP-1(1-37), GLP-1(7-37)and GLP-1(7-36)amide, as well as analogs of GLP-1) have been shown tostimulate insulin secretion (i.e., it is insulinotropic) which inducesglucose uptake by cells and results in decreases in serum glucose levels(see, e.g., Mojsov, S., Int. J. Peptide Protein Research, 40:333-343(1992)).

Numerous GLP-1 derivatives and analogues demonstrating insulinotropicaction are known in the art (see, e.g., U.S. Pat. Nos. 5,118,666;5,120,712; 5,512,549; 5,545,618; 5,574,008; 5,574,008; 5,614,492;5,958,909; 6,191,102; 6,268,343; 6,329,336; 6,451,974; 6,458,924;6,514,500; 6,593,295; 6,703,359; 6,706,689; 6,720,407; 6,821,949;6,849,708; 6,849,714; 6,887,470; 6,887,849; 6,903,186; 7,022,674;7,041,646; 7,084,243; 7,101,843; 7,138,486; 7,141,547; 7,144,863; and7,199,217). Accordingly, for ease of reference herein, the family ofGLP-1 derivatives and analogues having insulinotropic activity isreferred to collectively as GLP-1.

The exendins are peptides that were isolated from the venom of theGila-monster. Exendin-4 is present in the venom of Heloderma suspectum(Eng, J., et al., J. Biol. Chem., 265:20259-62 (1990); Eng., J., et al.,J. Biol. Chem., 267:7402-05 (1992); U.S. Pat. No. 5,424,286). Theexendins have some sequence similarity to several members of theglucagon like peptide family, with the highest homology, 53%, being toGLP-1(7-36)amide (Goke, et al., J. Biol. Chem., 268:19650-55 (1993)).

Exendin-4 acts at GLP-1 receptors on insulin-secreting beta-TC1 cells,dispersed acinar cells from guinea pig pancreas, and parietal cells fromstomach. The exendin-4 peptide also stimulates somatostatin release andinhibits gastrin release in isolated stomachs (Goke, et al., J. Biol.Chem. 268:19650-55 (1993); Schepp, et al., Eur. J. Pharmacol., 69:183-91(1994); Eissele, et al., Life Sci., 55:629-34 (1994)). Based on theirinsulinotropic activities, use of exendin-3 and exendin-4 for thetreatment of diabetes mellitus and the prevention of hyperglycemia hasbeen proposed (see, e.g., U.S. Pat. No. 5,424,286).

Exendin-4 has similar properties to GLP-1 in that, for example, itregulates gastric emptying, insulin secretion, food intake, and glucagonsecretion.

Numerous exendin-4 derivatives and analogues (including, e.g., exendin-4agonists) demonstrating insulinotropic action are known in the art (see,e.g., U.S. Pat. Nos. 5,424,286; 6,268,343; 6,329,336; 6,506,724;6,514,500; 6,528,486; 6,593,295; 6,703,359; 6,706,689; 6,767,887;6,821,949; 6,849,714; 6,858,576; 6,872,700; 6,887,470; 6,887,849;6,924,264; 6,956,026; 6,989,366; 7,022,674; 7,041,646; 7,115,569;7,138,375; 7,141,547; 7,153,825; and 7,157,555). Accordingly, for easeof reference herein, the family of exendin-4 derivatives and analogueshaving insulinotropic activity is referred to collectively as exendin-4.

The active agents can also be in various forms including, but notlimited to, the following: uncharged molecules; components of molecularcomplexes; and pharmacologically acceptable salts such as hydrochloride,hydrobromide, sulfate, laurates, palmatates, phosphate, nitrate, borate,acetate, maleate, tartrate, oleates, or salicylates. For acidic drugs,salts of metals, amines or organic cations, for example, quaternaryammonium, can be employed. Furthermore, simple derivatives of the drugsuch as esters, ethers, amides and the like that have solubilitycharacteristics suitable for the purpose of the invention can also beused herein. Drug or other formulation within the osmotic devicereservoir can have various art known forms such as solution, dispersion,paste, cream, particle, granule, tablet, emulsions, suspensions, powdersand the like. In addition to the one or more active agents, the activeagent formulation may optionally include pharmaceutically acceptablecarriers and/or additional ingredients such as antioxidants, stabilizingagents, buffers, and permeation enhancers.

The above agents are useful for the treatment of a variety of conditionsincluding but not limited to hemophilia and other blood disorders,growth disorders, diabetes, leukemia, hepatitis, renal failure,bacterial infection, viral infection (e.g., infection by HIV, HCV,etc.), hereditary diseases such as cerbrosidase deficiency and adenosinedeaminase deficiency, hypertension, septic shock, autoimmune diseases(e.g., Graves disease, systemic lupus erythematosus and rheumatoidarthritis), shock and wasting disorders, cystic fibrosis, lactoseintolerance, Crohn's diseases, inflammatory bowel disease,gastrointestinal and other cancers.

The amount of active or beneficial agent employed in the delivery deviceof the invention is that amount necessary to deliver a therapeuticallyeffective amount of the agent to achieve the desired therapeutic resultat the site of delivery. In practice, this will vary depending upon suchvariables, for example, as the particular agent, the site of delivery,the severity of the condition, and the desired therapeutic effect.Beneficial agents and their dosage unit amounts are known to the priorart in Goodman & Gilman's The Pharmacological Basis of Therapeutics,11th Ed., (2005), McGraw Hill; Remington's Pharmaceutical Sciences, 18thEd., (1995), Mack Publishing Co.; and Martin's Physical Pharmacy andPharmaceutical Sciences, 1.00 edition (2005), Lippincott Williams &Wilkins. Typically, for an osmotic delivery system, the volume of thechamber comprising the active agent formulation (e.g., chamber 108,FIG. 1) is between about 100 μl to about 1000 μl, more preferablybetween about 140 μl and about 200 μl. In one embodiment, the volume ofthe chamber comprising the active agent formulation is about 150 μl.

In one aspect, the present invention provides an active agentformulation of an interferon (e.g., alpha, beta, delta, gamma, lambda,omega or tau interferon), for example, a suspension formulationcomprising, a particle formulation comprising omega interferon and asuspension vehicle as described, for example, in published U.S PatentApplication Publication Nos. 2006-0263433 and 2006-0251618. Thesuspension vehicle typically comprises a non-aqueous, single-phasevehicle including one or more polymer and one or more solvent. Thevehicle preferably exhibits viscous fluid characteristics. The peptidecomponent comprises the interferon peptide in a particle formulationthat is dispersed in the vehicle. Typically, the particle formulationincludes a stabilizing component comprising one of more stabilizercomponent selected from the group consisting of carbohydrates,antioxidants, amino acids, buffers, and inorganic compounds.

3.4.1 Particle Formulations

Particle formulations used in the practice of the invention arepreferably chemically and physically stable for at least about 1 month,more preferably at least about 3 months, more preferably at least about6 months, and even more preferably at least about 12 months, at deliverytemperature. The delivery temperature is typically normal human bodytemperature, for example, about 37° C., or slightly higher, for example,about 40° C. Further, particle formulations of the present invention arepreferably chemically and physically stable for at least about 3 months,more preferably at least about 6 months, even more preferably at leastabout 12 months, at storage temperature. Examples of storagetemperatures include refrigeration temperature, for example, about 5°C., or room temperature, for example, about 25° C.

A particle formulation may be considered chemically stable if less thanabout 25%, preferably less than about 20%, more preferably less thanabout 15%, more preferably less than about 10%, and more preferably lessthan about 5% breakdown products of the peptide particles are formedafter about 3 months, preferably after about 6 months, preferably afterabout 12 months at delivery temperature and after about 6 months, afterabout 12 months, and preferably after about 24 months at storagetemperature.

A particle formulation may be considered physically stable if less thanabout 10%, preferably less than about 5%, more preferably less thanabout 3%, more preferably less than 1% aggregates of the peptideparticles are formed after about 3 months, preferably after about 6months, at delivery temperature and about 6 months, preferably about 12months, at storage temperature. Another criterion for demonstrating thata particle formulation is considered physically stable is that the solidstate of the particle can remain essentially the same or substantiallysimilar (for example, the particle does not demonstrate a phasetransition from amorphous to crystal or an inter-exchange betweenpolymorphous states) for a selected period of time (e.g., after about 3months, preferably after about 6 months, preferably after about 12months at delivery temperature and after about 6 months, preferablyafter about 12 months, and more preferably after about 24 months atstorage temperature).

To preserve protein stability generally a protein solution is kept in afrozen condition and lyophilized or spray dried to a solid state. Tg(glass transition temperature) may be one factor to consider inachieving stable compositions of protein. While not intending to bebound by any particular theory, the theory of formation of a high Tgamorphous solid to stabilize peptides, polypeptides, or proteins hasbeen utilized in pharmaceutical industry. Generally, if an amorphoussolid has a higher Tg, such as 100° C., protein products will not havemobility when stored at room temp or even at 40° C. because the storagetemperature is below the Tg. Calculations using molecular informationhave shown that if a glass transition temperature is above a storagetemperature of 50° C. that there is zero mobility for molecules. Nomobility of molecules correlates with no instability issues. Tg is alsodependent on the moisture level in the product formulation. Generally,the more moisture, the lower the Tg of the composition.

Accordingly, in some aspects of the present invention, excipients withhigher Tg may be included in the protein formulation to improvestability, for example, sucrose (Tg=75° C.) and trehalose (Tg=110° C.).Preferably, particle formulations are formable into particles usingprocesses such as spray drying, lyophilization, desiccation,freeze-drying, milling, granulation, ultrasonic drop creation,crystallization, precipitation, or other techniques available in the artfor forming particles from a mixture of components. The particles arepreferably substantially uniform in shape and size.

A typical spray dry process may include, for example, loading a spraysolution containing a peptide, for example, omega interferon, andstabilizing excipients into a sample chamber. The sample chamber istypically maintained at a desired temperature, for example,refrigeration to room temperature. Refrigeration generally promotesstability of the protein. A feed pump sprays the spray solution into anozzle atomizer. At the same time, atomized gas (typically, air,nitrogen, or inert gas) is directed at the outlet of the nozzle atomizerto form a mist of droplets from the spray solution. The mist of dropletsis immediately brought into contact with a drying gas in a dryingchamber. The drying gas removes solvent from the droplets and carriesthe particles into a collection chamber. In spray drying, factors thatcan affect yield include, but are not limited to, localized charges onparticles (which may promote adhesion of the particles to the spraydryer) and aerodynamics of the particles (which may make it difficult tocollect the particles). In general, yield of the spray dry processdepends in part on the particle formulation.

The particles are sized such that they can be delivered via an osmoticdelivery system of the present invention. Uniform shape and size of theparticles typically help to provide a consistent and uniform rate ofrelease from such a delivery system; however, a particle preparationhaving a non-normal particle size distribution profile may also be used.For example, in an osmotic delivery system as described herein having adelivery orifice 124 of FIG. 1, the size of the particles is less thanabout 30%, preferably is less than about 20%, preferably is less thanabout than 10%, and more preferably less than about 5% of the diameterof the delivery orifice.

In a preferred embodiment, when the particles are incorporated in asuspension vehicle they do not settle in less than about 3 months atdelivery temperature. Generally speaking, smaller particles tend to havea lower settling rate in viscous suspension vehicles than largerparticles. Accordingly, micron- to nano-sized particles are typicallydesirable. In an embodiment of the particle formulation for use with anosmotic delivery system, wherein the delivery orifice diameter of theimplant is in a range of, for example, about 0.1 to about 0.5 mm,particle sizes may be preferably less than about 50 microns, morepreferably less than about 10 microns, more preferably in a range fromabout 3 to about 7 microns. In one embodiment, the orifice is about 0.25mm (250 μm) and the particle size is approximately 3-5 μm.

In one embodiment, a particle formulation of the present inventioncomprises one or more interferon peptides (e.g., alpha, beta, delta,gamma, lambda, omega or tau interferon), one or more stabilizers, andoptionally a buffer. The stabilizers may be, for example, carbohydrate,antioxidant, amino acid, buffer, or inorganic compound. The amounts ofstabilizers and buffer in the particle formulation can be determinedexperimentally based on the activities of the stabilizers and buffersand the desired characteristics of the formulation. Typically, theamount of carbohydrate in the formulation is determined by aggregationconcerns. In general, the carbohydrate level is not be too high so as toavoid promoting crystal growth in the presence of water due to excesscarbohydrate unbound to the peptide. Typically, the amount ofantioxidant in the formulation is determined by oxidation concerns,while the amount of amino acid in the formulation is determined byoxidation concerns and/or formability of particles during spray drying.Typically, the amount of buffer in the formulation is determined bypre-processing concerns, stability concerns, and formability ofparticles during spray drying. Buffer may be required to stabilize thepeptide during processing, e.g., solution preparation and spray drying,when all excipients are solubilized.

Examples of carbohydrates that may be included in the particleformulation include, but are not limited to, monosaccharides (e.g.,fructose, maltose, galactose, glucose, D-mannose, and sorbose),disaccharides (e.g., lactose, sucrose, trehalose, and cellobiose),polysaccharides (e.g., raffinose, melezitose, maltodextrins, dextrans,and starches), and alditols (acyclic polyols; e.g., mannitol, xylitol,maltitol, lactitol, xylitol sorbitol, pyranosyl sorbitol, andmyoinsitol). Preferred carbohydrates include non-reducing sugars such assucrose, trehalose, and raffinose.

Examples of antioxidants that may be included in the particleformulation include, but are not limited to, methionine, ascorbic acid,sodium thiosulfate, catalase, platinum, ethylenediaminetetraacetic acid(EDTA), citric acid, cysteins, thioglycerol, thioglycolic acid,thiosorbitol, butylated hydroxanisol, butylated hydroxyltoluene, andpropyl gallate.

Examples of amino acids that may be included in the particle formulationinclude, but are not limited to, arginine, methionine, glycine,histidine, alanine, L-leucine, glutamic acid, iso-leucine, L-threonine,2-phenylamine, valine, norvaline, praline, phenylalanine, tryptophan,serine, asparagines, cysteine, tyrosine, lysine, and norleucine.Preferred amino acids include those that readily oxidize, e.g.,cysteine, methionine, and tryptophan.

Examples of buffers that may be included in the particle formulationinclude, but are not limited to, citrate, histidine, succinate,phosphate, maleate, tris, acetate, carbohydrate, and gly-gly. Preferredbuffers include citrate, histidine, succinate, and tris.

Examples of inorganic compounds that may be included in the particleformulation include, but are not limited to, NaCl, NaSCN, Na₂SO4,NaHCO₃, KCl, KH₂PO4, CaCl₂, and MgCl₂.

In addition, the particle formulation may include other excipients suchas surfactants, bulking agents, and salts. Examples of surfactantsinclude, but are not limited to, Polysorbate 20, Polysorbate 80,PLURONIC® (BASF Corporation, Mount Olive N.J.) F68, and sodium docecylsulfate (SDS). Examples of bulking agents include, but are not limitedto, mannitol and glycine. Examples of salts include, but are not limitedto, sodium chloride, calcium chloride, and magnesium chloride.

3.4.2 Vehicle Formulations

In one aspect of the present invention, a suspension vehicle provides astable environment in which a particle formulation is dispersed. Thesuspension vehicle typically comprises one or more polymer and one ormore solvent that form a solution of sufficient viscosity to uniformlysuspend the particles comprising the peptide. The piston assemblies ofthe present invention, as described herein above, are substantiallyimpermeable to and substantially resistant to leaching when exposed tothe vehicle, particularly to the organic solvent of the vehicle.

The viscosity of the suspension vehicle is typically sufficient toprevent the particle formulation from settling during storage and use ina method of delivery, for example, in the osmotic delivery system. Thesuspension vehicle is biodegradable in that the suspension vehicledisintegrates or breaks down over a period of time in response to abiological environment. The disintegration of the suspension vehicle mayoccur by one or more physical or chemical degradative processes such asby enzymatic action, oxidation, reduction, hydrolysis (e.g.,proteolysis), displacement (e.g., ion exchange), or dissolution bysolubilization, emulsion or micelle formation. After the suspensionvehicle disintegrates, components of the suspension vehicle are absorbedor otherwise dissipated by the body and surrounding tissue of thesubject.

The solvent in which the polymer is dissolved may affect characteristicsof the suspension formulation such as the behavior of the peptideparticle formulation during storage. A solvent may be selected incombination with a polymer so that the resulting suspension vehicleexhibits phase separation upon contact with the aqueous environment.Optionally, the solvent may be selected in combination with the polymerso that the resulting suspension vehicle exhibits phase separation uponcontact with the aqueous environment having less than approximatelyabout 10% water.

In some embodiments, the solvent may be an acceptable solvent that isnot miscible with water. The solvent may also be selected so that thepolymer is soluble in the solvent at high concentrations such as at apolymer concentration of greater than about 30%. However, typically thepeptide is substantially insoluble in the solvent. Examples of solventsuseful in the practice of the present invention include, but are notlimited to, lauryl alcohol, benzyl benzoate, benzyl alcohol, lauryllactate, decanol (also called decyl alcohol), ethyl hexyl lactate, andlong chain (C₈ to C₂₄) aliphatic alcohols, esters, or mixtures thereof.The solvent used in the suspension vehicle may be “dry,” in that it hasa low moisture content. Preferred solvents for use in formulation of thesuspension vehicle include lauryl lactate, lauryl alcohol, and benzylbenzoate.

Additional solvents that may be useful in the practice of the presentinvention include, but are not limited to, the following: vegetable oils(sesame oil, cottonseed oil, soybean oil); triglycerides; glycerin;glycerol; polyethylene glycol (e.g., PEG400); glycofurol;N-methylpyrrolidone; polysorbates (e.g., polysorbate 20 and polysorbate80); alpha-tocopherol (e.g., Vitamin E); dimethyl sulfoxide; or siliconmedical fluid.

Examples of polymers for formulation of the suspension vehicles of thepresent invention include, but are not limited to, a polyester (e.g.,polylactic acid or polylacticpolyglycolic acid), pyrrolidone (e.g.,polyvinylpyrrolidone (PVP) having a molecular weight ranging fromapproximately 2,000 to approximately 1,000,000), ester or ether of anunsaturated alcohol (e.g., vinyl acetate),polyoxyethylenepolyoxypropylene block copolymer, or mixtures thereof. Inone embodiment, the polymer is PVP having a molecular weight of 2,000 to1,000,000. The polymer used in the suspension vehicle may include one ormore different polymers or may include different grades of a singlepolymer. The polymer used in the suspension vehicle may also be dry orhave a low moisture content.

Generally speaking, a suspension vehicle according to the presentinvention may vary in composition based on the desired performancecharacteristics. In one embodiment, the suspension vehicle may compriseabout 25 wt % to about 80 wt % polymer and about 75 wt % to about 20 wt% solvent, more preferably 40 wt % to about 75 wt % polymer and about 60wt % to about 25 wt % solvent. Preferred embodiments of a suspensionvehicle include vehicles formed of polymer and solvent combined at thefollowing ratios: about 75 wt % polymer and about 25 wt % solvent; about60 wt % polymer and about 40 wt % solvent; about 55 wt % polymer andabout 45 wt % solvent; about 50 wt % polymer and about 50 wt % solvent;about 45 wt % polymer and about 55 wt % solvent; about 40 wt % polymerand about 60 wt % solvent; and about 25 wt % polymer and about 75 wt %solvent.

The suspension vehicle may exhibit Newtonian behavior. The suspensionvehicle is typically formulated to provide a viscosity that maintains auniform dispersion of the particle formulation for a predeterminedperiod of time in a suspension formulation. This helps facilitate makinga suspension formulation tailored to provide controlled delivery of thepeptide at a desired rate. The viscosity of the suspension vehicle mayvary depending on the desired application, the size and type of theparticle formulation, and the loading of the particle formulation in thesuspension vehicle. The viscosity of the suspension vehicle may bevaried by altering the type or relative amount of the solvent or polymerused.

The suspension vehicle may have a viscosity ranging from about 100 poiseto about 1,000,000 poise, preferably from about 1,000 poise to about100,000 poise. The viscosity may be measured at 37° C., at a shear rateof 10⁻⁴/sec, using a parallel plate rheometer. In one embodiment, theviscosity of the suspension vehicle ranges from approximately 5,000poise to approximately 50,000 poise. In one embodiment, the vehicle hasa viscosity of about 16,700 poise at 33° C. In preferred embodiments,the viscosity range is between about 12,000 to about 18,000 poise at 33°C.

The suspension vehicle may exhibit phase separation when contacted withthe aqueous environment. However, typically the suspension vehicleexhibits substantially no phase separation as a function of temperature.For example, at a temperature ranging from approximately 0° C. toapproximately 70° C. and upon temperature cycling, such as cycling from4° C. to 37° C. to 4° C., the suspension vehicle typically exhibits nophase separation. In some embodiments of the invention, the suspensionvehicle exhibits phase separation when contacted with the aqueousenvironment having less than approximately 10% water.

The suspension vehicle may be, for example, prepared by combining thepolymer and the solvent under dry conditions such as in a dry box. Thepolymer and solvent may be combined at an elevated temperature, forexample, from approximately 40° C. to approximately 70° C., and allowedto liquefy and form the single phase. The ingredients may be blendedunder vacuum to remove air bubbles produced from the dry ingredients.The ingredients may be combined using a conventional mixer such as adual helix blade or similar mixer, for example, set at a speed ofapproximately 40 rpm. However, higher speeds may also be used to mix theingredients. Once a liquid solution of the ingredients is achieved, thesuspension vehicle may be cooled to room temperature. Differentialscanning calorimetry (DSC) may be used to verify that the suspensionvehicle is a single phase. Further, the components of the suspensionvehicle (e.g., the solvent and/or the polymer) may be treated tosubstantially reduce or substantially remove peroxides.

The particle formulation, comprising a peptide (e.g., omega interferon),is added to the suspension vehicle to form a suspension formulation. Thesuspension formulation may be prepared by dispersing the particleformulation in the suspension vehicle. The suspension vehicle may beheated and the particle formulation added to the suspension vehicleunder dry conditions. The ingredients may be mixed under vacuum at anelevated temperature such as from about 40° C. to about 70° C. Theingredients may be mixed at a sufficient speed such as from about 40 rpmto about 120 rpm, and for a sufficient amount of time, for example,about 15 minutes, to achieve a uniform dispersion of the particleformulation in the suspension vehicle. The mixer may be a dual helixblade or other suitable mixer. The resulting mixture may be removed fromthe mixer, sealed in a dry container to prevent water from contaminatingthe suspension formulation, and allowed to cool to room temperaturebefore further use, for example, loading into an osmotic deliverysystem.

The suspension formulation typically has an overall moisture content ofless than about 10 wt %, preferably less than about 5 wt %, and morepreferably less than about 4 wt %.

In summary, the components of the suspension vehicle providebiocompatibility with the subject in whom use is intended. Components ofthe suspension vehicle offer suitable chemico-physical properties toform stable suspensions of, for example, dry powder particleformulations. These properties include, but are not limited to, thefollowing: viscosity of the suspension; purity of the vehicle; residualmoisture of the vehicle; density of the vehicle; compatibility with thedry powders; compatibility with implantable devices; molecular weight ofthe polymer; stability of the vehicle; and hydrophobicity andhydrophilicity of the vehicle. These properties can be manipulated andcontrolled, for example, by variation of the vehicle composition andmanipulation of the ratio of components used in the suspension vehicle.

All components included in the particle formulation are typicallyacceptable for pharmaceutical use in subjects, particularly humans.

One embodiment of the present invention includes an osmotic deliverysystem as described herein, comprising an suspension formulation asfollows: an omega interferon particle formulation (omegainterferon:sucrose:methionine:citrate in a ratio of 1:2:1:2.15 byweight) suspended in a benzyl benzoate/polyvinylpyrrolidone (BB/PVP)suspension vehicle with a target particle loading of approximately 10%(w/w). Reservoirs of the osmotic delivery system are filled withapproximately 150 μL of the suspension.

3.5.0 Reservoir

Materials that may be used for the reservoir (e.g., 102, FIG. 1) aresufficiently rigid to withstand expansion of the osmotic agentformulation (e.g., 114, FIG. 1) without changing its size or shape.Where the osmotic delivery system is implantable, the materials aretypically selected to ensure that the reservoir will not leak, crack,break, or distort under stresses to which it may be subjected duringimplantation or under stresses due to the pressures generated duringoperation. The reservoir may be formed of non-reactive (or inert),biocompatible, natural or synthetic materials which are known in theart. The material of the reservoir may be non-bioerodible (i.e., notsoluble in a fluid environment of use, e.g., gastric fluid) or may bebioerodible (i.e., soluble in a fluid environment of use, e.g., gastricfluid). Preferably, the material of the reservoir is non-bioerodible.Generally, preferred materials for the reservoir are those acceptablefor human implantation. Preferably, the material of the reservoir isimpermeable, particularly when stability of the formulation in thereservoir is sensitive to fluids in the fluid environment of use (e.g.,after implantation in a subject).

Examples of materials suitable for the reservoir include non-reactive,biocompatible polymers and metals or alloys. Examples of non-reactive,biocompatible polymers for the reservoir include, but are not limitedto, acrylonitrile polymers such as acrylonitrile-butadiene-styreneterpolymer; halogenated polymers such as polytetrafluoroethylene,polychlorotrifluoroethylene, copolymer tetrafluoroethylene andhexafluoropropylene; polyimide; polysulfone; polycarbonate;polyethylene; polypropylene; polyvinylchloride-acrylic copolymer;polycarbonate-acrylonitrile-butadiene-styrene; and polystyrene. Examplesof metallic, biocompatible materials for the reservoir 102 include, butare not limited to, stainless steel, titanium, platinum, tantalum, gold,and their alloys, as well as gold-plated ferrous alloys, platinum-platedferrous alloys, cobalt-chromium alloys and titanium nitride coatedstainless steel. For size-critical applications, high payloadcapability, long duration applications, and applications where theformulation is sensitive to body chemistry at the implantation site, thereservoir is preferably made of titanium or a titanium alloy havinggreater than about 60%, more preferably greater than about 85% titanium.

The body of the reservoir may be labeled, for example, using laseretching, to indicate the nature of the active agent, dosage of theactive agent, manufacturer, and the like. In addition, the body of thereservoir may comprise a marking, for example, a grooved band, toprovide directional orientation to the user for the product, forexample, a grooved band may be asymmetrically placed relative to themid-point of the body of the reservoir to indicate which end of thereservoir comprises the semipermeable membrane or the flow modulator.Such a groove is particularly useful when both ends of the body of thereservoir are similar in appearance.

The total size of the reservoir is selected based on a variety ofparameters, for example, (i) the volume occupied by a flow modulator(e.g., FIG. 1, flow modulator 120), (ii) the volume occupied by anactive agent formulation (e.g., FIG. 1, chamber 108), (iii) the volumeoccupied by a piston assembly (e.g., FIG. 1, piston assembly 200), (iv)the volume occupied by an osmotic agent formulation (e.g., FIG. 1,osmotic agent formulation 114), (v) the volume occupied by asemipermeable membrane (e.g., FIG. 1 semipermeable membrane 116), and(vi) the amount of active agent being delivered and the period of timeover which the osmotic delivery system will be delivering the activeagent. Typically, the total reservoir volume (i.e., the volume definedby interior chamber of the reservoir in the absence of other components)is between about 200 μl to about 2000 μl, more preferably between about250 μl and about 400 μl. In one embodiment, the total reservoir volumeis about 300 μl.

3.6.0 Flow Modulator and Orifice

The flow modulator is typically a plug-like member defining a liquidflow path for exit of the active agent from the osmotic delivery system(see, e.g., U.S. Pat. Nos. 5,728,396, 5,997,527, 6,217,906, 6,287,295,6,395,292, 6,524,305, 6,635,268, 6,840,931, and 6,923,800).

The invention is not limited to any particular flow modulator as long asthe flow modulator is able to deliver the active agent formulation in adesired manner. Preferably, the flow modulator (e.g., 120, FIG. 1)allows delivery of the active agent formulation (e.g., 112, FIG. 1)while controlling back-diffusion of external fluid into the lumen (e.g.,104, FIG. 1). The end (e.g., 122, FIG. 1) may be open and the flowmodulator (e.g., 120, FIG. 1) may be provided in the form of a plugwhich is inserted in the open end. Alternately, the flow modulator(e.g., 120, FIG. 1) may be integrated with the end (e.g., 122, FIG. 1)of the reservoir (e.g., 102, FIG. 1).

The delivery orifice flow channel provided by the flow modulator may be,for example, spiral in shape or straight. Further, the orifice flowchannel may be of a variety of shapes including, but not limited to,circular, triangular, square, D-shaped, oval, or elongated (e.g.,slit-like). The flow modulator is preferably made of a non-reactive (orinert), biocompatible material. Exemplary materials include, but are notlimited to, metals such as titanium, stainless steel, platinum and theiralloys, and cobalt-chromium alloys. Other compatible materials includepolymers such as polyethylene, polypropylene, polycarbonate,polymethylmethacrylate, and polyaryletherketones, e.g.,polyetheretherketone (PEEK). In one embodiment, the orifice flow channelis a D-shaped channel having a nominal “diameter” (i.e., measured acrossthe widest opening) of 250 μm (0.25 mm).

The flow modulator may be assembled to the reservoir by using a numberof methods, for example, a thread and screw method wherein the flowmodulator or the interior surface of the lumen or both comprise ribs,for example, complementary continuous helical threads/grooves. Single,double, triple, or quadruple threads/grooves may be used.

Alternatively, the flow modulator may be assembled to the reservoir by apress-fit (i.e., interference fit) where the outside of the flowmodulator is slightly larger than the inside diameter of the reservoir.Typically, this assembly method is faster and easier to automate thanother assembly methods that may be used in the practice of the presentinvention such as thread and screw assemblies.

A variety of types of delivery orifices are known in the art and usefulin the practice of the present invention. For example, a flexible flowmoderator may have at least one slit orifice which is in fluidcommunication with the chamber comprising the active agent. The slitorifice may be, for example, closed when the pressure of the fluid inthe active agent chamber is less than a predetermined pressure (see,e.g., U.S. Pat. No. 5,997,527). The slit orifice may open only to theminimum dimension required to allow the flow generated by the osmoticpumping rate (see, e.g., U.S. Pat. No. 6,217,906).

An osmotic delivery system flow modulator assembly may also include, forexample, a body defining an open pathway (e.g., a hole or flow channel)through the body of the flow modulator that communicates between twoopposing ends of the body (e.g., where the orifice defines the exit siteof the active agent). The open pathway may be, for example, straight,spiral, or curved. The flow modulator may further comprise a stopperthat serves to close the orifice to the external environment until theosmotic delivery system is ready for use (see, e.g., U.S. Pat. No.6,524,305). Prior to use, for example, insertion of an implantableosmotic delivery system into a subject, such a stopper is removed.

In one embodiment, the flow moderator comprises two polyetheretherketonemachined parts, an inner core and an outer sleeve, whereby a continuousspiral delivery channel is formed between the two parts when they areassembled. The two-piece moderator is assembled by press-fitting intothe reservoir (wherein neither the reservoir nor the moderator comprisesribs). In other embodiments, ribbed components may be used.

The present invention also includes methods of manufacturing the osmoticdelivery systems of the present invention, comprising assembly of theabove-described components.

Furthermore, the osmotic delivery systems of the present invention maybe individually packaged or packaged in groups. Such packaging may be,for example, foil pouches or vials. The packaging may include adesiccant or the osmotic delivery systems may be packaged under nitrogenor vacuum.

4.0.0 Uses of the Osmotic Delivery System

In one aspect, the present invention provides methods of treatment for asubject comprising administering to a subject in need of treatment anactive agent using the osmotic delivery system described herein above.Typically, the osmotic delivery system is implanted in the subject suchthat the system is in contact with a fluid environment within thesubject.

The osmotic delivery system of the present invention allows the deliveryof an active agent to a subject in a controlled manner over a prolongedperiod without intervention. Sustained delivery of an active agent canimprove the therapeutic effect of the active agent by reduction orelimination of peak plasma-level related effects (e.g., of multiplebolus injections), often associated with toxicities, as well assub-therapeutic troughs, often associated with suboptimal therapeuticeffects. This improved therapeutic effect may include, for example,potentially minimizing systemic side effects. Sustained delivery of anactive agent without intervention can be provided by, for example,implanting in a subject one or more osmotic delivery system describedherein.

Such implantable osmotic delivery systems can be designed to providetherapeutic doses of the drug over periods of weeks, months, or even ayear or more. Implantable osmotic delivery systems once inserted in asubject are not easily tampered with by the subject. Accordingly,compliance to a required dosing regimen is generally assured.

A subject being treated with the suspension formulations of the presentinvention, for example, delivered to the subject from an implantedosmotic delivery system, may also benefit from co-treatment with otheragents such as small molecules. In one embodiment, when the osmoticdelivery system of the present invention is used to deliver aninterferon, co-treatment may include treatment with an inosinemonophosphate dehydrogenase inhibitor (e.g., ribavirin, a ribavirinanalog, mycophenolic acid, mycophenolate mofetil, mycophenolic acidsodium, aminothiadiazole, thiophenfurin, tiazofurin, and/or viramidine).

In one embodiment, the invention relates to a method of treating aninterferon-responsive disorder comprising administering to a subject asuspension formulation described above (e.g., comprising an interferon,for the treatment of HCV or multiple sclerosis; for example, omegainterferon, beta interferon, alpha interferon or pegylated alphainterferon for the treatment of HCV; or beta interferon for thetreatment of multiple sclerosis). This improved therapeutic effect may,for example potentially minimize known systemic side effects ofinterferon treatment such as fatigue and flu-like symptoms.

Certain interferons are used for treatment of certain viral infections(e.g., infection by HCV or HIV), multiple sclerosis, and certaincancers. Many disease states require long-term treatment with aparticular interferon. Accordingly, the osmotic delivery system of thepresent invention coupled with the suspension formulations describedherein above may provide a convenient and effective alternative torepeated dosing with, for example, injectable formulations ofinterferon. Treatment of interferon-responsive disorders using theosmotic delivery system of the present invention comprising a suspensionformulation comprising an interferon may also include co-treatment withother beneficial active agents (e.g., ribavirin in the case of viralinfections).

In one aspect, the present invention includes a method of treating viralinfection, for example, infection with HCV, in a subject in need of suchtreatment, comprising administering a therapeutically effective amountof interferon to the subject over time, wherein the interferon is, forexample, alpha, beta, or omega interferon and is administered using animplanted osmotic delivery system. In one embodiment, the osmoticdelivery system is designed to provide a volumetric flow rate (μl/day)of about 1.3 to about 1.7 μl/day. This corresponds to a cumulativeprotein (e.g., of omega interferon) release of about 120 to about 230micrograms during the time period of day 14 to 21 of operation of theosmotic delivery system after implantation in a subject. Typically, thetime course for delivery is about 90 days, with an additionalapproximately 10 days of operation to provide some flexibility for thesubject being treated.

In another aspect, the present invention includes a method of treatingmultiple sclerosis in a subject in need of such treatment, comprisingadministering a therapeutically effective amount of interferon to thesubject over time, wherein the interferon is administered using animplanted osmotic delivery system. In one embodiment the interferon isbeta or omega interferon.

In yet another aspect, the present invention includes a method oftreating diabetes or diabetes-related disorders in a subject in need ofsuch treatment, comprising administering a therapeutically effectiveamount of an insulinotropic peptide to the subject over time, whereinthe insulinotropic peptide is administered using an implanted osmoticdelivery system. In one embodiment the insulinotropic peptide is a GLP-1peptide (including GLP-1 analogs or derivatives) or an exendin-4 peptide(including exendin-4 analogs or derivatives).

Aspects of the present invention are described herein below withreference to an osmotic delivery system comprising omega interferon asan active agent. These examples are not intended to be limiting.

Other objects may be apparent to one of ordinary skill upon reviewingthe following specification and claims.

EXPERIMENTAL

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the devices, methods, and formulae of the presentinvention, and are not intended to limit the scope of what the inventorregards as the invention. Efforts have been made to ensure accuracy withrespect to numbers used (e.g., amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

The compositions produced according to the present invention meet thespecifications for content and purity required of pharmaceuticalproducts.

Example 1 Osmotic Delivery System Assembly

An osmotic delivery system, as illustrated in FIG. 1, containing omegainterferon for the treatment of, for example, HCV infection, wasassembled from the following components: (i) reservoir made of implantgrade titanium alloy and having undercuts at an end thereof, (ii)osmotic active formulation in the form of two cylindrical tablets, eachtablet including primarily sodium chloride salt with cellulosic andpovidone binders, (iii) piston assembly as described in FIG. 2A made ofultra-high molecular weight polyethylene, (iv) semipermeable membranemade of polyurethane and having four retaining ribs that mate withundercuts in reservoir, (v) flow modulator having a spiral orifice, and(vi) an active agent formulation comprising a suspension formulation,comprising a particle formulation (omega interferon, sucrose,methionine, citric acid monohydrate, and sodium citrate) in a suspensionvehicle (benzyl benzoate and povidone).

Example 2 Cumulative Release Rate of Omega Interferon

Reservoirs of several osmotic delivery systems, as described in EXAMPLE1, were filled with 150-μL of the suspension formulation, as describedin EXAMPLE 1. The semipermeable membrane ends of the osmotic deliverysystems were placed into stoppered glass vials filled with 3 mLphosphate buffer solution (PBS), and the flow modulator ends of theosmotic delivery systems were placed into glass vials filled with 2.5 to3 mL release rate medium (citrate buffer solution at pH 6.0 with 0.14 MNaCl and 0.2% sodium azide). The systems were placed into capped testtubes, with the flow modulator side down, and partially immersed in a37° C. water bath. At specified time points, the glass vials at the flowmodulator ends were replaced with new glass vials filled with 2.5 to 3mL release rate medium (citrate buffer solution at pH 6.0 with 0.14 MNaCl and 0.2% sodium azide). Samples were collected from the flowmodulator ends and analyzed using Reversed Phase High Performance LiquidChromatography (RP-HPLC). FIG. 3 shows the cumulative release rate ofomega interferon formulation as a function of time over 120 days. InFIG. 3, the vertical axis represents the percent cumulative release(Cumulative Release (%)) and the horizontal axis represents time in days(Time (day)).

The vertical axis in FIG. 3 represents the range zero to 100% ofcumulative active agent delivered from the osmotic system. These dataillustrate that osmotic delivery systems comprising the pistonassemblies of the present invention provide pharmaceutically acceptablecontinuous, linear sustained release of an active agent for the intendedduration of delivery. The osmotic systems of FIG. 3 were designed todeliver an active agent for a minimum of 100 days.

Example 3 Evaluation of Leachates Released to Solvent

Flow modulators made of polyetheretherketone (PEEK) were inserted atends of reservoirs made of titanium alloy. Piston assemblies,essentially as shown and described in FIG. 2A, made of ultra-highmolecular weight polyethylene were placed in the lumen of thereservoirs. 100% benzyl benzoate solvent was loaded into the lumens ofthe reservoirs in contact with the flow modulators and the pistonassemblies. The systems were stored at 40° C. for 3 months and sampledat 0, 45, and 90 days. The samples were analyzed by chromatic techniquesto determine if volatile or non-volatile leachates were present in thebenzyl benzoate. The limit of quantification (LOQ) for volatileleachates was 1.4 μg/ml and for non-volatile leachates was 9.0 μg/ml.The results of the analyses are presented in Table 2 below.

TABLE 2 t = 0 days t = 45 days t = 90 days Volatile leachates, μg/ml (n= 3) <1.4 <1.4 <1.4 Non-volatile leachates, μg/ml <9 <9 <9 (n = 3)

These data illustrate that use of the piston assemblies of the presentinvention, for example, piston assembly as described in FIG. 2A made ofultra-high molecular weight polyethylene, when employed in osmoticdelivery systems are resistant to leaching and result in levels ofvolatile and non-volatile leachates that are below quantifiable limitsand below maximum allowable limits that are pharmaceutically acceptable.

Example 4 Comparison of Leachates Released to Solvent from PistonAssemblies Made of Fluorosilicone

Flow modulators made of polyetheretherketone (PEEK) were inserted atends of reservoirs made of titanium alloy. Conventional pistons made offluorosilicone were placed in the lumen of the reservoirs. 100% benzylbenzoate solvent was loaded into the lumens of the reservoirs in contactwith the flow modulators and the conventional pistons. The systems werestored at 40° C. for 3 months and sampled at 0, 45, and 90 days. Thesamples were analyzed by chromatic techniques to determine if volatileor non-volatile leachates were present in the benzyl benzoate. The limitof quantification (LOQ) for volatile leachates was 1.4 μg/ml and fornon-volatile leachates was 9.0 μg/ml. The results of the analyses arepresented in Table 3 below.

TABLE 3 t = 0 days t = 45 days t = 90 days Volatile leachates, μg/ml (n= 3) <1.4  3.7 (avg) <1.4 Non-volatile leachates, μg/ml 56 (avg) 283(avg) 408 (avg) (n = 3)

These data illustrate that use of the piston assemblies of the presentinvention, for example, piston assembly as described in FIG. 2A made ofultra-high molecular weight polyethylene, when employed in osmoticdelivery systems provide superior performance in regard to resistance toleaching, resulting in lower levels of volatile and non-volatileleachates (e.g., see data in Table 2) relative to conventional pistons,for example, comprising fluorosilicone (e.g., compare data in Table 2and Table 3).

As is apparent to one of skill in the art, various modification andvariations of the above embodiments can be made without departing fromthe spirit and scope of this invention. Such modifications andvariations are within the scope of this invention.

1.-27. (canceled)
 28. A piston assembly for positioning in a lumen of areservoir of an osmotic delivery system, comprising a columnar body andone or more O-rings, wherein (i) the columnar body and one or moreO-rings are constructed and arranged for positioning in the lumen, (ii)the columnar body has a core made of a first material that is anincompressible material, (iii) the columnar body further comprises oneor more concentric grooves, and (iv) each groove retains one of the oneor more O-rings and each of the one or more O-rings are made of a secondmaterial that is an elastomeric material.
 29. The piston assemblyaccording to claim 28, wherein the elastomeric material comprises aperfluoroelastomer.
 30. The piston assembly according to claim 28,wherein the incompressible material is chosen from an ultra highmolecular weight polyethylene and polyaryletherketone.
 31. The pistonassembly according to claim 30, wherein the polyaryletherketone ischosen from polyetherketone and polyetheretherketone.
 32. The pistonassembly according to claim 30, wherein the incompressible materialproduces volatile leachates of less than 1.4 μg/mL when exposed tobenzyl benzoate at 40° C. for at least 45 days.
 33. The piston assemblyaccording to claim 28, wherein each O-ring engages and maintains a sealagainst the inner wall of the reservoir.
 34. The piston assemblyaccording to claim 33, wherein the piston assembly is movable within thereservoir in response to pressure within the reservoir.
 35. The pistonassembly according to claim 32, wherein the incompressible materialproduces volatile leachates of less than 1.4 μg/mL when exposed tobenzyl benzoate at 40° C. for about 90 days.
 36. The piston assemblyaccording to claim 32, wherein the incompressible material producesvolatile leachates of less than 1.4 μg/mL when exposed to benzylbenzoate at 40° C. for longer than 90 days.
 37. The piston assemblyaccording to claim 28, wherein the osmotic delivery system is an osmoticdelivery system for delivering an active agent formulation to a fluidenvironment.
 38. The piston assembly according to claim 37, wherein theosmotic delivery system further comprises a semipermeable membranepositioned at a first end of the reservoir adjacent an osmotic agentformulation.
 39. The piston assembly according to claim 37, wherein theosmotic delivery system further comprises a flow modulator positioned ata second end of the reservoir adjacent the active agent formulation, theflow modulator having an orifice for delivering the active agentformulation to the fluid environment.
 40. The piston assembly accordingto claim 37, wherein the active agent formulation comprises a particleformulation comprising active agent, and a suspension vehicle comprisingone or more organic solvent.
 41. The piston assembly according to claim40, wherein the organic solvent is chosen from benzyl benzoate, lauryllactate, and lauryl alcohol.
 42. The piston assembly according to claim40, wherein the active agent in the particle formulation is chosen froma peptide, a polypeptide, and a protein.
 43. The piston assemblyaccording to claim 42, wherein the polypeptide is chosen from glucagonlike protein (GLP-1), GLP-1 derivative polypeptides and analogpolypeptides, exendin-4, and exendin-4 derivative polypeptides andanalog polypeptides.